JP2011506318A - Oral pharmaceutical formulation - Google Patents

Abstract

An abuse-resistant oral preparation suitable for administration of a pharmacologically active agent is provided.
[Selection] Figure 23

Description

  The present invention relates to oral pharmaceutical formulations and uses thereof. More particularly, the present invention relates to abuse-resistant oral pharmaceutical formulations and their use for delivering pharmacologically active agents.

  Techniques and compositions for drug delivery of pharmaceuticals, including oral delivery, are well known. For example, antihistamines, decongestants, and antacids are all generally delivered in the form of solid tablets. Analgesics such as salicylic acid, morphine, Demerol ™ (meperidine), codeine, and Percocet ™ (oxycodone) have been delivered orally in tablet form for many years. Controlled and sustained release pharmaceutical compositions have also been available for many years, including, for example, Contac 400 Time Capsule ™ (phenylpropanolamine hydrochloride and chlorpheniramine maleate), antipsychotics, melatonin The formulation provides release of the active agent over several hours. Analgesics are of particular interest as controlled release formulations, and general controlled release formulations of analgesics include OxyContin® (oxycodone), MS Contin ™ (morphine), CS Continent. (Trademark) (codeine).

  The formulation of drugs that are subject to delivery, particularly oral delivery, has several challenges. One challenge is to create an orally controlled release formulation that provides a relatively steady dose of drug over a period of about 8 hours during which the formulation passes through the gastrointestinal tract. Sustained release is often achieved by applying a coating that delays release to the tablet, or by formulating the tablet to disintegrate relatively slowly to release the drug during that time. However, since tablets are subject to significant mechanical and chemical stresses after ingestion as they pass through the esophagus, stomach, duodenum, jejunum, ileum, large intestine, and colon, they can maintain controlled release of the drug product It creates considerable challenges. Acids, enzymes, and peristalsis can break the tablet apart, exposing the inside of the tablet and increasing the surface area of the tablet material. In this case, the delivery rate of the drug will be likely to increase, or otherwise the controlled release of the formulation will be susceptible to adverse effects.

  Another challenge is making a formulation that reduces the potential for drug abuse, such as an oral formulation. In particular, opioids, CNS inhibitors, and stimulants are commonly abused. According to a 1999 study by the National Institute on Drug Abuse (NIDA), an estimated 4 million people, equivalent to about 2 percent of the population over 12 years of age, are using prescription drugs “non-medical” (At the time of survey). Of this, 2.6 million people abused analgesics, 1.3 million people abused sedatives and tranquilizers, and 900,000 people abused stimulants.

  Although many prescription drugs can be abused, the most common abuse drug classes are (1) opioids (often prescribed to treat pain), (2) CNS inhibitors (Used to treat anxiety and sleep disorders), and (3) stimulants (prescribed to treat narcolepsy and attention / hyperactivity disorder).

  Opioids are powerful anesthetics and examples include morphine, codeine, oxycodone, and fentanyl, and related drugs. Morphine is often used to relieve severe pain. Codeine is used for milder pain. Other examples of opioids that may be prescribed to relieve pain include oxycodone (eg, OxyContin®, an oral controlled release formulation of this drug), propoxyphene (eg, Darvon ™ )), Hydrocodone (eg, Vicodin ™), hydromorphone (eg, Diaudidid ™), and meperidine (eg, Demerol ™). In addition to reducing pain, opioids can also cause euphoria and, when taken in large amounts, can cause severe respiratory depression that can lead to death.

  CNS inhibitors slow down normal brain function by increasing GABA activity, thereby causing a sedative or sedative effect. At higher doses, some CNS inhibitors can become general anesthetics, and at very high doses can cause respiratory failure and death. CNS inhibitors are frequently abused, and in many cases, abuse of CNS inhibitors occurs in conjunction with the abuse of other substances or drugs such as alcohol or cocaine. Many deaths occur each year due to such drug abuse. CNS inhibitors are based on their chemistry and pharmacology in two groups: (1) barbiturates such as mefobarbital (eg Mebaral ™) and pentobarbital sodium (eg Nembutal ™) ( These are used to treat anxiety, tension, and sleep disorders), (2) benzodiazepines, such as diazepam (eg, Valium ™), chlordiazepoxide HCl (eg, Librium ™), and alprazolam ( For example, Xanax ™), which can be prescribed to treat anxiety, acute stress responses, and panic attacks. Benzodiazepines that have a stronger sedative effect, such as triazolam (eg, Halcion ™) and estazolam (eg, ProSom ™) may be prescribed for short-term treatment of sleep disorders.

  Stimulants are a class of drugs that enhance brain activity, causing alertness, attention, and increased vitality with increased blood pressure, heart rate, and respiration. Stimulants are frequently prescribed to treat narcolepsy, attention deficit hyperactivity disorder (ADHD), and depression. Stimulants may also be used for short-term treatment of obesity and asthmatic patients. Stimulants such as dextroamphetamine (Dexedrine ™) and methylphenidate (Ritalin ™) have chemical structures similar to the major brain neurotransmitters called monoamines, including norepinephrine and dopamine . Stimulants increase the levels of these chemicals in the brain and in the body. This results in increased blood pressure and heart rate, vasoconstriction, increased blood sugar, and enlarged respiratory pathways. In addition, increased dopamine is associated with the euphoria that can accompany the use of such drugs. Taking high doses of stimulants can cause irregular heartbeats, dangerous hyperthermia, and / or the possibility of cardiovascular failure or fatal seizures. Ingestion of high doses of several stimulants over a short period of time may cause hostility or paranoia in some people.

  Well-known and particularly dangerous drug cocktails are produced when stimulants are mixed with antidepressants or when they are mixed with commercial cold medicines that contain a decongestant. Antidepressants can enhance the effects of stimulants, and stimulants combined with decongestants can cause blood pressure to be dangerously high or cause irregular heartbeat rhythms. In some cases, it can lead to death.

  Solid formulations are particularly susceptible to abuse. For example, tablets for oral drug delivery can be ground into a powder. Drug addicts and drug abusers grind the tablets into pieces for nasal inhalation of the drug. Addictives also grind the tablets to extract the drug into alcohol or water to make a concentrated drug solution for injection. When various drugs of abuse are administered in this manner, a high dose of the drug is suddenly generated in the bloodstream, resulting in euphoria for the user. These well-known approaches for drug abuse have been used for many years on all types of drugs.

  One particularly important example of a highly addictive drug that is often abused by crushing (for nasal inhalation) and / or alcohol or water extraction (for intravenous injection) is oxycodone. Oxycodone is a powerful analgesic. This analgesic is available in the form of extended release tablets (OxyContin®, Purdue Pharmaceuticals) and is manufactured with tablet content of 10 mg, 20 mg, 40 mg, and 80 mg (160 mg tablet content is (Recovered from the US market due to the prevalence of abuse of this particular formulation content and the abuse of such high doses of oxycodone could be dangerous). OxyContin® tablets are formulated as time-release tablets (approximately 12 hours release), but of course, their controlled release is impaired by tablet crushing or crushing. In 2004, 36,600 people visited the emergency room in the United States as a result of oxycodone abuse, of which 20,000 are due to abuse of sustained-release oxycodone formulations (eg, OxyContin® tablets) I know that. Intentional abuse of oxycodone has reached a significant rate in the United States, and according to the 2004 National Survey on Drug Use and Health, 3.1 million Americans use sustained release oxycodone for non-medical purposes. Furthermore, deaths from unintentional overdose of opioid analgesics show an increase of more than 18% annually from 1990 to 2002, with 5528 more opioid analgesics in that period than either heroin or cocaine. Listed in death certificate. Chewing / nasal inhalation of crushed 40 mg OxyContin® is the same as ingesting 8 tablets of Percocet® at once, and for 80 mg OxyContin®, 16 tablets of Percocet® Equivalent to taking all of the trademark) at once. Overdose causes small pupils, exhalation, dizziness, weakness, seizures, loss of consciousness, coma, and sometimes death.

  Abuse-resistant oral pharmaceutical formulations comprising a pharmacologically active agent and a controlled release carrier system are provided. Accordingly, it is an object of the present invention to provide an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes a high viscosity liquid carrier material (“HVLCM”), a network former, a rheology modifier, a hydrophilic agent, and a solvent. The object of the invention is also that the in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food, or conversely, the in vivo release of the active agent from the controlled release carrier system is It is to provide a formulation as described above that is substantially free of food effects. A related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg reduced such misuse or abuse. The risk made does not have any significant effect on the absorption of the active agent from the formulation when the in vitro solvent extraction rate of the active agent from the formulation is low and / or when the subject ingests the formulation and alcohol simultaneously It is characterized by For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including specific combinations of solvents, viscosity enhancing agents, and the like. Controlled release carrier systems impart abuse resistance to the formulation. Accordingly, a related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system also comprises one or more of the following additional ingredients: viscosity enhancers and stabilizers. is there. In certain embodiments, the HVLCM can comprise sucrose acetate isobutyrate (“SAIB”) and the network former is cellulose acetate butyrate (“CAB”), cellulose acetate phthalate, ethyl cellulose, hydroxy Propylmethylcellulose, or cellulose triacetate, and rheology modifiers include isopropyl myristate (“IPM”), caprylic / capric triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate, or benzyl benzoate. Hydrophilic agents can be included and include hydroxyethyl cellulose ("HEC"), hydroxypropyl cellulose, carboxymethyl cellulose, polyethylene glycol, or polyvinyl It may include a pyrrolidone, and solvent can include triacetin, N- methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, or glycofurol. In addition, the viscosity enhancer can include silicon dioxide, and the stabilizer can include butylhydroxyl toluene ("BHT"). In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

  Another object of the present invention is to provide an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. The controlled release carrier system includes a high viscosity liquid carrier material (“HVLCM”), a network former, at least one viscosity enhancer, a hydrophilic solvent, and a hydrophobic solvent. The object of the invention is also that the in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food, or conversely, the in vivo release of the active agent from the controlled release carrier system is It is to provide a formulation as described above that is substantially free of food effects. A related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg reduced such misuse or abuse. The risk made does not have any significant effect on the absorption of the active agent from the formulation when the in vitro solvent extraction rate of the active agent from the formulation is low and / or when the subject ingests the formulation and alcohol simultaneously It is characterized by For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including specific combinations of solvents, viscosity enhancing agents, and the like. Controlled release carrier systems impart abuse resistance to the formulation. In certain preferred embodiments, the network former can include CAB, cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, or cellulose triacetate, and the first viscosity enhancing agent is HEC, hydroxypropyl cellulose, Carboxymethyl cellulose, polyethylene glycol, or polyvinyl pyrrolidone can be included, and hydrophilic solvents include triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, or glycofurol. And the hydrophobic solvent can comprise IPM. In addition, the active agent can be an opioid, CNS inhibitor, or CNS stimulant that is particularly likely to be abused, diverted, or otherwise misused. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

  Another object of the present invention is to provide a process for preparing an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes a high viscosity liquid carrier material (“HVLCM”), a network former, a rheology modifier, a hydrophilic agent, and a solvent. The manufacturing or compounding process comprises the following steps: preheating the HVLCM, mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent, and a network former. A step of dispersing in the solution and dissolving the network-forming agent in the solution, and 5-30% of the rheology modifier, or optionally a solution of 5-30% of the stabilizer and the rheology modifier, Add the step of mixing with the formulation, adding and mixing the pharmacologically active agent, adding and mixing the hydrophilic agent, optionally adding and mixing the viscosity enhancing agent, and adding the rest of the rheology modifier Adding and mixing. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle. A related object of the present invention is to provide a process for preparing an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes HVLCM, a network former, a rheology modifier, a hydrophilic agent, and a solvent. The manufacturing or compounding process is optionally stabilized by the following steps: preheating the HVLCM, mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent. Mixing the 5% to 30% solution of the agent with the rheology modifier with the solution obtained in the previous step, and the rheology modifier, or if the previous step is performed (if step), the rest of the rheology modifier A step of adding and mixing a portion of the above with the solution obtained in the previous step, and optionally adding and mixing a viscosity enhancer with the formulation obtained in the previous step, and a network structure in the solution thus obtained. A step of dissolving the network-forming agent in the solution by adding and dispersing the forming agent, a step of adding and mixing the pharmacologically active agent with the formulation obtained in the previous step, a step of adding and mixing the hydrophilic agent, including. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle. A related object of the present invention is to provide an oral pharmaceutical preparation obtainable by the above manufacturing process or blending process.

  Another object of the present invention is to provide a process for preparing an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent, and a hydrophobic solvent. The manufacturing or compounding process comprises the following steps: preheating the HVLCM, mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent, and a network former. A step of dispersing in the solution and dissolving the network-forming agent in the solution, and 5-30% of the rheology modifier, or optionally a solution of 5-30% of the stabilizer and the rheology modifier, Add the step of mixing with the formulation, adding and mixing the pharmacologically active agent, adding and mixing the hydrophilic agent, optionally adding and mixing the viscosity enhancing agent, and adding the rest of the rheology modifier Adding and mixing. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle. A related object of the present invention is to provide a process for preparing an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent, and a hydrophobic solvent. The manufacturing or compounding process is optionally stabilized by the following steps: preheating the HVLCM, mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent. Mixing the solution of 5-30% of the agent and rheology modifier with the solution obtained in the previous step, and the rheology modifier, or if the previous step is performed, the remaining part of the rheology modifier, A step of adding and mixing with the solution obtained in the previous step, and optionally a step of adding and mixing a viscosity enhancer with the formulation obtained in the previous step, and adding a network-forming agent to the solution thus obtained It includes a step of dissolving the network-forming agent in the solution by dispersing, a step of adding and mixing the pharmacologically active agent with the blend obtained in the previous step, and a step of adding and mixing the hydrophilic agent. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle. A related object of the present invention is to provide an oral pharmaceutical preparation obtainable by the above manufacturing process or blending process.

A further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. Controlled release carrier systems provide controlled in vivo release of agents characterized by steady state C _min / C _max variations within each dosing interval that are less than or equal to the therapeutic index of the active agent. It is also an object of the invention to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the formulation is suitable for use in a BID dosing regimen. A related object of the present invention is characterized in that the in vivo pharmacological performance has a respective steady state _Cmin / _Cmax variation that is about 2-3 or less when administered at a therapeutically effective dose or AUC. It is to provide a formulation as described above. A related object of the present invention is also to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg such misuse or abuse. The reduced risk has any significant effect on the in vitro solvent extraction rate of the active agent from the formulation and / or any absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Characterized by not having. For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients comprising a solvent, a carrier material, and a viscosity enhancing agent. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

A further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. The controlled release carrier system is such that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent, and in vivo absorption of the active agent from the formulation is administered with food. Although enhanced, it provides for controlled in vivo release of the agent, characterized by the formulation still being safe even when ingested without following the formula, for example without food. It is also an object of the present invention to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the formulation is suitable for use in a BID dosing regimen, and in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food. A related object of the present invention is to provide a formulation as described above, characterized in that the in vivo pharmacological performance has a respective steady state _Cmin / _Cmax variation of about 2-3 or less. It is. A related object of the present invention is also to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg such misuse or abuse. The reduced risk has any significant effect on the in vitro solvent extraction rate of the active agent from the formulation and / or any absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Characterized by not having. For each related object of the invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including a solvent, a carrier material, a network former, and a viscosity enhancing agent. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

Another further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising an opioid analgesic and a controlled release carrier system. The controlled release carrier system has a steady state C _min / C _max variation within each dose interval that is less than or equal to the therapeutic index of the active agent, and pharmacokinetic in vivo release of the opioid analgesic from the controlled release carrier system. Provides controlled in vivo release of the agent characterized by performance being characterized by a T _max of at least about 4 hours after ingestion by the subject. It is also an object of the present invention to provide an abuse-resistant oral pharmaceutical formulation comprising an opioid analgesic and a controlled release carrier system. However, the formulation is suitable for use in a BID dosing regimen, and the pharmacokinetic in vivo release performance of the opioid analgesic from the controlled release carrier system is at least about 4 hours after ingestion by the subject. It is characterized by T _max. A related object of the present invention is that the in vivo absorption of the opioid analgesic from the formulation is enhanced when the formulation is administered with food or, conversely, the in vivo release of the opioid analgesic from the controlled release carrier system. Is to provide a formulation as described above that is substantially free of food effects. A further related object of the present invention provides a formulation as described above, characterized in that the in vivo pharmacological performance has a respective steady state C _min / C _max variation that is about 2-3 or less. it is. A related object of the present invention is also to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg such misuse or abuse. The reduced risk is any significant effect on the in vitro solvent extraction rate of the opioid analgesic from the formulation and / or the absorption of the opioid analgesic from the formulation when the subject takes the formulation and alcohol at the same time. It is characterized by not adversely also. For each related object of the invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including a solvent, a carrier material, a network former, and a viscosity enhancing agent.

Another further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. The controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent, and the carrier system comprises a high viscosity liquid carrier material (“HVLCM”) and a reticulated Providing controlled in vivo release of an agent characterized by comprising a structure-forming agent and at least one viscosity enhancing agent. It is also an object of the present invention to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the formulation is suitable for use in a BID dosing regimen, and further, the controlled release carrier system comprises a high viscosity liquid carrier material (“HVLCM”), a network former, and at least one viscosity enhancement. An agent. A related object of the present invention is that the in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food, or conversely, the in vivo release of the active agent from the controlled release carrier system is It is to provide a formulation as described above that is substantially free of food effects. A related object of the present invention is to provide a formulation as described above, characterized in that the in vivo pharmacological performance has a respective steady state _Cmin / _Cmax variation of about 2-3 or less. It is. A related object of the present invention is also to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg such misuse or abuse. The reduced risk has any significant effect on the in vitro solvent extraction rate of the active agent from the formulation and / or any absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Characterized by not having. For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including specific combinations of solvents, viscosity enhancers and the like. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

It is also an object of the present invention to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. Controlled release carrier systems have a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent, and more specifically, each steady state C _min / C _max variation is about Provide controlled in vivo release of the agent, characterized in that it is 2-3 or less. It is also an object of the present invention to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the formulation is suitable for use in a BID dosing regimen, and further, the pharmacokinetic in vivo release performance of the active agent from the controlled release carrier system is at least about 4 hours after ingestion by the subject. It is characterized by _max. A related object of the present invention is that the in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food, or conversely, the in vivo release of the active agent from the controlled release carrier system is It is to provide a formulation as described above that is substantially free of food effects. A related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg reduced such misuse or abuse. The risk made does not have any significant impact on the absorption of the active agent from the formulation when the in vitro solvent extraction rate of the active agent from the formulation is low and / or when the subject ingests the formulation and alcohol simultaneously characterized by. For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including specific combinations of solvents, viscosity enhancers and the like. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

  A further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. The controlled release carrier system includes a high viscosity liquid carrier material (“HVLCM”), a network former, and at least one viscosity enhancer. The object of the invention is also that the in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food, or conversely, the in vivo release of the active agent from the controlled release carrier system is It is to provide a formulation as described above that is substantially free of food effects. A related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse, eg reduced such misuse or abuse. The risk made does not have any significant effect on the absorption of the active agent from the formulation when the in vitro solvent extraction rate of the active agent from the formulation is low and / or when the subject ingests the formulation and alcohol simultaneously It is characterized by For each related object of the present invention described above, the controlled release carrier system may be further characterized by a unique group of pharmaceutical excipients including specific combinations of solvents, viscosity enhancing agents, and the like. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base.

  Another further object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the carrier system is substantially at least 8 hours when tested on a USP Type II Dissolution Apparatus with a fixed basket assembly using a paddle speed of 100 rpm and a 0.1 N HCl dissolution medium containing a surfactant. Provides a constant in vitro active agent release and less than 20% of the active agent can be extracted from the formulation in a 1 hour in vitro solvent extraction test using EtOH (100 proof) as the extraction solvent at ambient temperature (RT) It is. A related object of the present invention is to provide an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the carrier system is substantially at least 8 hours when tested on a USP Type II Dissolution Apparatus with a fixed basket assembly using a paddle speed of 100 rpm and a 0.1 N HCl dissolution medium containing a surfactant. Provides a constant in vitro active agent release, and up to 30% of the active agent can be extracted from the formulation in a one hour in vitro solvent extraction test using a group of extraction solvents at ambient temperature (RT).

  A further object of the present invention is to provide an oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system. However, the controlled release carrier system includes HVLCM, a network former, a rheology modifier, and a hydrophilic agent, and the formulation is abuse-resistant. A related object of the present invention is to provide a formulation as described above, wherein the controlled release carrier system also comprises one or more of the following additional ingredients: a viscosity enhancer, a solvent, and a stabilizer. It is. In certain embodiments, the HVLCM can include sucrose acetate isobutyrate (“SAIB”), and the network former can include cellulose acetate butyrate (“CAB”); The rheology modifier can include isopropyl myristate (“IPM”) and the hydrophilic agent can include hydroxyethyl cellulose (“HEC”), and therefore also functions as a viscosity enhancer. The viscosity enhancing agent can also be silicon dioxide, the stabilizer can comprise butylhydroxyl toluene ("BHT"), and the activator can be a salt or Opioids can be included as either free base.

  Another object of the present invention is to provide a controlled release oral pharmaceutical formulation comprising an opioid active agent. However, the formulation provides effective analgesia to subjects when administered on a twice daily (BID) dosing schedule, and the formulation can be evaluated using the following abuse-resistant performance characteristics (method of Example 4) One or more of (A) When subjected to extraction into 100 proof ethanol over 5 minutes at room temperature, the formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid. (B) When subjected to extraction in vinegar for 5 minutes at room temperature, the formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid. (C) The formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at room temperature for 5 minutes. (D) When subjected to extraction into a cola soft drink for 5 minutes at room temperature, the formulation releases less than about 10% of the opioid, preferably less than about 5% of the opioid. (E) When subjected to extraction into 100 proof ethanol for 60 minutes at room temperature, the formulation releases less than about 20% of the opioid, preferably less than about 11% of the opioid. (F) When subjected to extraction into vinegar for 60 minutes at room temperature, the formulation releases less than about 20% of the opioid, preferably less than about 12% of the opioid. (G) When subjected to extraction into a saturated sodium bicarbonate solution at room temperature for 60 minutes, the formulation releases less than about 20% of the opioid, preferably less than about 12% of the opioid. (H) When subjected to extraction into a cola soft drink for 60 minutes at room temperature, the formulation releases less than about 30% of the opioid, preferably less than about 22% of the opioid. (I) When subjected to extraction in 100 proof ethanol for 5 minutes at 60 ° C., the formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid. (J) When subjected to extraction into vinegar at 60 ° C. for 5 minutes, the formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid. (K) The formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 ° C. for 5 minutes. (L) When subjected to extraction into a cola soft drink at 60 ° C. for 5 minutes, the formulation releases less than about 45% of the opioid, preferably less than about 30% of the opioid. (M) When subjected to extraction into 100 proof ethanol for 60 minutes at 60 ° C., the formulation releases less than about 33% of the opioid, preferably less than about 26% of the opioid. (N) When subjected to extraction into vinegar at 60 ° C. for 60 minutes, the formulation releases less than about 33% of the opioid, preferably less than about 20% of the opioid. (O) The formulation releases less than about 33% of the opioid, preferably less than about 23% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 ° C. for 60 minutes. (P) When subjected to extraction into a cola soft drink at 60 ° C. for 60 minutes, the formulation releases less than about 60% of the opioid, preferably less than about 45% of the opioid. (Q) less than about 20% of the opioid, preferably less of the opioid when subjected to extraction into a group of extraction solvents containing vinegar, hot tea, saturated baking soda, and cola soft drink for 60 minutes each at 25 ° C. Release less than about 15%. (R) Releases less than about 15% of the opioid, preferably less than about 12% of the opioid when subjected to extraction into a group of aqueous buffered extraction solutions in the range of pH 1 to pH 12, each at 25 ° C. for 60 minutes. To do. (S) A group of physically breaking the formulation by crushing, each containing 60 ° C. water at 25 ° C., 60-70 ° C. water, 0.1 N HCL at 25 ° C., and 100 proof ethanol at 25 ° C. for 60 minutes each Releases less than about 40% of the opioid, preferably less than about 35% of the opioid when subjected to extraction into an aqueous extraction solution. And / or (t) physically destroy the formulation by microwave treatment and then into a group of aqueous extraction solutions containing water, 0.1 N HCL, and 100 proof ethanol each for 60 minutes at 25 ° C. When subjected to extraction, release less than about 25% of the opioid, preferably less than about 20% of the opioid. In certain embodiments, the opioid is oxycodone, oxymorphone, hydrocodone, or hydromorphone and can exist in either a salt form or a free base form. In one preferred embodiment, the opioid is oxycodone.

Another further object of the present invention is to provide safer treatment methods (including palliative care) to patients in need of such treatment. This method requires administration of an abuse-resistant oral pharmaceutical formulation according to the present invention. More specifically, an object of the present invention is to provide a method for ensuring and maintaining analgesia in a subject by repeated administration of an oral analgesic formulation. However, the formulation is resistant to abuse and thus provides a safer method of treatment. The formulation used in this method comprises a controlled release carrier system and an analgesic, and the controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is below the therapeutic index of the analgesic. Providing controlled in vivo release of analgesics characterized in that The object of the present invention is also to provide a method for ensuring and maintaining analgesia in a subject by repeated administration of oral analgesic preparations. However, the formulation is abuse-resistant and is suitable for use in a BID dosing regimen. A related object of the present invention is to provide a method wherein the in vivo pharmacological performance of the formulation is characterized by having a respective steady state C _min / C _max variation that is about 2-3 or less. . A related object of the present invention is also to provide a formulation as described above in which the controlled release carrier system further provides a reduced risk of misuse or abuse, eg, reduced such misuse or abuse. The risk is that the in vitro solvent extraction rate of the analgesic from the formulation is low and / or does not have any significant effect on the absorption of the analgesic from the formulation when the subject takes the formulation and alcohol at the same time. Is characterized by Another further related object of the present invention is to provide a method of ensuring and maintaining analgesia in a subject by repeated administration of an abuse-resistant oral analgesic formulation. However, the bioavailability of analgesics is enhanced when the formulation is co-administered with food (eg, increasing the in vivo absorption of the agent from the formulation). In certain embodiments, the method requires repeated administration of the above formulation, wherein the analgesic is an opioid, and in a preferred embodiment, the opioid is present in the formulation in its free base form.

Another object of the present invention is to provide a method for ensuring and maintaining analgesia in a subject by repeated administration of an oral analgesic preparation. However, the formulation includes a controlled release carrier system and an analgesic agent, and the controlled release carrier system includes HVLCM, a network former, and at least one viscosity enhancer. For the related purposes of the present invention, the formulation provides a safer method of treatment and is therefore abuse resistant. Another related object is to provide a method for ensuring and maintaining analgesia in a subject by repeated administration of oral analgesic formulations. Wherein the formulation further provides controlled in vivo release of the analgesic, characterized in that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the analgesic. Sex carrier system. The object of the present invention is also to provide a method for ensuring and maintaining analgesia in a subject by repeated administration of oral analgesic preparations. However, the formulation is suitable for use in a BID dosing regimen. A related object of the present invention is to provide a method wherein the in vivo pharmacological performance of the formulation is characterized by having a respective steady state C _min / C _max variation that is about 2-3 or less. . A related object of the present invention is also to provide a formulation as described above in which the controlled release carrier system further provides a reduced risk of misuse or abuse, eg, reduced such misuse or abuse. The risk is that the in vitro solvent extraction rate of the analgesic from the formulation is low and / or does not have any significant effect on the absorption of the analgesic from the formulation when the subject takes the formulation and alcohol at the same time. Is characterized by Another further related object of the present invention is to provide a method of ensuring and maintaining analgesia in a subject by repeated administration of an abuse-resistant oral analgesic formulation. However, the bioavailability of analgesics is enhanced when the formulation is co-administered with food (eg, increasing the in vivo absorption of the agent from the formulation). In certain embodiments, the method requires repeated administration of the above formulation, wherein the analgesic is an opioid, and in a preferred embodiment, the opioid is present in the formulation in its free base form.

  It is an advantage of the present invention that an abuse-resistant oral formulation can provide enhanced safety properties and / or abuse resistance in addition to enhanced in vivo pharmacological performance compared to conventional formulations. . It is a further advantage of the present invention that dosage formulations according to the present invention can be readily constructed and used to provide the medical field with a broader, safer and more effective pharmacological solution. These and other objects, aspects, and advantages of the present invention will be apparent to those of ordinary skill in the art upon reading this disclosure and the specification.

Items of the present invention A pharmacologically active agent;
・ High viscosity liquid carrier material (HVLCM),
・ Network-former,
・ Rheology modifier,
A hydrophilic agent, and a solvent,
An oral pharmaceutical formulation comprising: a controlled release carrier system comprising:

  2. Item 2. The preparation according to Item 1, wherein the pharmacologically active agent is an opioid, a central nervous system (CNS) inhibitor, or a CNS stimulant.

  3. Item 3. The formulation of item 2, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone in either the free base form or a pharmaceutically acceptable salt form thereof.

  4). Item 3. The formulation according to Item 2, wherein the pharmacologically active agent is selected from amphetamine, methylphenidate, and pharmaceutically acceptable salts thereof.

5). HVLCM is sucrose acetate isobutyrate (SAIB),
The network former is selected from cellulose acetate butyrate (CAB), cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, and cellulose triacetate;
The rheology modifier is selected from isopropyl myristate (IPM), caprylic / capric triglycerides, ethyl oleate, triethyl citrate, dimethyl phthalate, and benzyl benzoate;
The hydrophilic agent is selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose, carboxymethyl cellulose, polyethylene glycol, and polyvinyl pyrrolidone, and the solvent is triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl Selected from lactate, propylene carbonate, and glycofurol,
The preparation according to any one of the preceding items.

  6). (A) HVLCM is SAIB, (b) the network-forming agent is CAB, (c) the rheology modifier is IPM, (d) the hydrophilic agent is HEC, and (e) the solvent is triacetin. The preparation according to item 5, wherein

  7. (A) 1.3-35 wt% pharmacologically active agent, (b) 2-10 wt% network-forming agent, (c) 0.1-20 wt% rheology modifier, (d) 1-8 wt A formulation according to any one of the preceding items comprising:% hydrophilic agent; (e) 10-40 wt% solvent; and (f) 30-60 wt% HVLCM.

  8). The formulation of any one of the preceding items, wherein the controlled release carrier system further comprises a viscosity enhancing agent.

  9. Item 9. The preparation according to Item 8, wherein the viscosity enhancer is silicon dioxide.

10. A pharmacologically active agent;
・ HVLCM,
・ Network-former,
A first viscosity enhancer,
A hydrophilic solvent, and a hydrophobic solvent,
An oral pharmaceutical formulation comprising: a controlled release carrier system comprising:

  11. Item 11. The preparation according to Item 10, wherein the pharmacologically active agent is an opioid, a central nervous system (CNS) inhibitor, or a CNS stimulant.

  12 Item 12. The formulation of item 11, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone in either the free base form or a pharmaceutically acceptable salt form thereof.

  13. Item 12. The formulation according to Item 11, wherein the pharmacologically active agent is selected from amphetamine, methylphenidate, and pharmaceutically acceptable salts thereof.

14 HVLCM is SAIB,
The network former is selected from CAB, cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, and cellulose triacetate;
The first viscosity enhancer is HEC, hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone;
The hydrophilic solvent is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, and glycofurol, and the hydrophobic solvent is IPM,
A formulation according to any one of items 10-13.

  15. (A) HVLCM is SAIB, (b) the network-forming agent is CAB, (c) the first viscosity enhancer is HEC, (d) the hydrophilic solvent is triacetin, and (e) Item 15. The preparation according to Item 14, wherein the hydrophobic solvent is IPM.

  16. (A) 1.3-35 wt% pharmacologically active agent, (b) 2-10 wt% network-forming agent, (c) 1-8 wt% first viscosity enhancer, (d) 10-10 The formulation according to any one of items 10 to 15, comprising 40 wt% hydrophilic solvent, (e) 0.1 to 20 wt% hydrophobic solvent, and (f) 30 to 60 wt% HVLCM. .

  17. The formulation according to any one of items 10 to 16, further comprising a second viscosity enhancer.

  18. Item 18. The formulation according to Item 17, wherein the second viscosity enhancing agent is silicone dioxide.

  19. The formulation according to any one of the preceding items, further comprising a stabilizer.

  20. Item 20. The formulation according to Item 19, wherein the stabilizer is butylhydroxyl toluene (BHT).

  21. At least 8 when tested on a USP Type II Dissolution Apparatus equipped with a stainless steel stationary basket assembly using a paddle speed of 100 rpm and 0.1 N HCl dissolution medium containing 0.5% sodium lauryl sulfate. Providing substantially constant in vitro active agent release over time and no more than 20% of the active agent is extracted from the formulation after 1 hour extraction in 100 proof ethanol (EtOH) at ambient temperature; The preparation according to any one of the preceding items.

  22. Less than 20% of the active agent is extracted after 60 minutes extraction into 100 proof EtOH at ambient temperature and less than 30% after 60 minutes extraction into 100 proof EtOH at 60 ° C. The formulation according to any one of the items.

  23. A formulation according to any one of the preceding items, wherein the formulation of active agent and carrier system is encapsulated in a capsule.

  24. 24. The formulation of item 23, wherein the capsule comprises gelatin, hydroxyethyl cellulose, or hydroxypropyl methylcellulose.

  25. 25. The formulation of item 23 or 24, wherein the capsule is packaged in a single dose blister or a multi-dose plastic bottle.

26. A process for preparing an oral pharmaceutical formulation as defined in item 1,
(I) preheating the HVLCM;
(Ii) mixing the solvent with preheated HVLCM to form a homogeneous solution of HVLCM in the solvent;
(Iii) dissolving the network former in the solution by dispersing the network former in the solution;
(Iv) mixing 5-30% of the rheology modifier, or optionally a solution of 5-30% of the stabilizer and the rheology modifier, with the formulation obtained in step (iii);
(V) mixing a pharmacologically active agent with the formulation obtained in step (iv);
(Vi) mixing a hydrophilic agent with the formulation obtained in step (v);
(Vii) optionally mixing a viscosity enhancing agent with the formulation obtained in step (vi);
(Viii) mixing the remaining part of the rheology modifier with the formulation obtained in step (vi) or, if step (vii) is performed, with the formulation obtained in step (vii). When,
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

27. A process for preparing an oral pharmaceutical formulation as defined in item 1,
(I) preheating the HVLCM;
(Ii) mixing the solvent with preheated HVLCM to form a homogeneous solution of HVLCM in the solvent;
(Iii) optionally mixing a solution of stabilizer and 5-30% of the rheology modifier with the solution obtained in step (ii);
(Iv) mixing the rheology modifier or, if step (iii) is performed, mixing the remaining part of the rheology modifier with the solution obtained in step (ii) or (iii);
(V) optionally mixing a viscosity enhancer with the formulation obtained in step (iv);
(Vi) In the solution by dispersing the network-forming agent in the solution obtained in step (iv) or, if step (v) is performed, in the solution obtained in step (v). Dissolving the network-forming agent in
(Vii) mixing a pharmacologically active agent with the formulation obtained in step (vi);
(Viii) mixing a hydrophilic agent with the formulation obtained in step (vii);
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

28. A process for preparing an oral pharmaceutical formulation as defined in item 10, comprising:
(I) preheating the HVLCM;
(Ii) forming a homogeneous solution of HVLCM in the solvent by mixing the hydrophilic solvent with the preheated HVLCM;
(Iii) dissolving the network former in the solution by dispersing the network former in the solution;
(Iv) mixing 5-30% of the hydrophobic solvent, or optionally a solution of stabilizer and 5-30% of the hydrophobic solvent with the formulation obtained in step (iii);
(V) mixing a pharmacologically active agent with the formulation obtained in step (iv);
(Vi) mixing the first viscosity enhancer with the formulation obtained in step (v);
(Vii) optionally mixing a second viscosity enhancer with the formulation obtained in step (vi);
(Viii) mixing the remaining part of the hydrophobic solvent with the formulation obtained in step (vi) or, if step (vii) is performed, with the formulation obtained in step (vii). When,
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

29. A process for preparing an oral pharmaceutical formulation as defined in item 10, comprising:
(I) preheating the HVLCM;
(Ii) forming a homogeneous solution of HVLCM in the solvent by mixing the hydrophilic solvent with the preheated HVLCM;
(Iii) optionally mixing a solution of stabilizer and 5-30% of the hydrophobic solvent with the solution obtained in step (ii);
(Iv) mixing the hydrophobic solvent or, if step (iii) has been performed, mixing the remaining part of the hydrophobic solvent with the solution obtained in step (ii) or (iii);
(V) optionally mixing a second viscosity enhancer with the formulation obtained in step (iv);
(Vi) In the solution by dispersing the network-forming agent in the solution obtained in step (iv) or, if step (v) is performed, in the solution obtained in step (v). Dissolving the network-forming agent in
(Vii) mixing a pharmacologically active agent with the formulation obtained in step (vi);
(Viii) mixing a first viscosity enhancer with the formulation obtained in step (vii);
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

  30. An oral pharmaceutical formulation obtainable by the process defined in any one of items 26-29.

31. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The pharmaceutical formulation is resistant to abuse, and the controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent Providing controlled in vivo release of the agent;
The above preparation.

  32. 32. The formulation of item 31, wherein the active agent is suspended in a controlled release carrier system.

33. 32. The formulation of item 31, wherein each steady state C _min / C _max variation is about 2-3 or less.

  34. 32. A formulation according to item 31, which is suitable for use in a BID dosing regimen.

  35. 32. A formulation according to item 31, wherein the active agent is an opioid.

  36. 32. The formulation of item 31, wherein the active agent is in salt form.

  37. 32. The formulation of item 31, wherein the controlled release carrier system comprises HVLCM and a network former.

  38. 40. The formulation of item 37, wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients.

  39. 40. The formulation of item 37, wherein the controlled release carrier system further comprises a plurality of viscosity enhancing agents.

  40. 40. The formulation of item 37, wherein the controlled release carrier system further comprises a plurality of solvents.

  41. 41. The formulation of item 40, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  42. 32. The formulation of item 31, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  43. 43. A formulation according to item 42, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  44. 43. Item 42. The reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  45. Item 44. The reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

46. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The pharmaceutical preparation is abuse-resistant,
The controlled release carrier system provides controlled in vivo release of the agent characterized in that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent; and In vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food;
The above preparation.

  47. 47. A formulation according to item 46, wherein the active agent is suspended in a controlled release carrier system.

48. 47. The formulation of item 46, wherein each steady state C _min / C _max variation is about 2-3 or less.

  49. 47. A formulation according to item 46, suitable for use in a BID dosing regimen.

  50. 47. A formulation according to item 46, wherein the active agent is an opioid.

  51. 47. A formulation according to item 46, wherein the active agent is in the free base form.

  52. 47. A formulation according to item 46, wherein the controlled release carrier system comprises HVLCM and a network former.

  53. 53. The formulation of item 52, wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients.

  54. 53. The formulation of item 52, wherein the controlled release carrier system further comprises a plurality of viscosity enhancing agents.

  55. 53. The formulation of item 52, wherein the controlled release carrier system further comprises a plurality of solvents.

  56. The formulation according to item 55, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  57. 47. The formulation of item 46, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  58. 58. The formulation of item 57, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  59. 58. The item 57, wherein the reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol simultaneously. Formulation.

  60. Item 60. The reduced risk of misuse or abuse is further characterized by not having any significant effect on absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  61. 49. A method of increasing the oral bioavailability of an active agent to a subject undergoing treatment with an active agent, the method comprising orally administering to the subject the formulation of item 46 with food.

  62. 49. A method for increasing the extent of absorption of an active agent from an oral formulation, the method comprising orally administering to a subject the formulation of item 46 with food.

63. An oral pharmaceutical formulation comprising an opioid analgesic and a controlled release carrier system comprising:
The pharmaceutical preparation is abuse-resistant,
The controlled release carrier system provides controlled in vivo release of the agent characterized in that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent; and The pharmacokinetic in vivo release performance of the opioid analgesic from a controlled release carrier system is characterized by a T _max of at least about 4 hours after ingestion by the subject.
The above preparation.

  64. 64. The formulation of item 63, wherein the opioid analgesic is suspended in the carrier system.

65. 64. The formulation of item 63, wherein each steady state C _min / C _max variation is about 2-3 or less.

  66. 64. The formulation of item 63, suitable for use in a BID dosing regimen.

  67. 64. A formulation according to item 63, wherein the opioid analgesic is in a salt form.

  68. 64. A formulation according to item 63, wherein the opioid analgesic is in a free base form.

  69. 64. The formulation of item 63, wherein the controlled release carrier system comprises HVLCM and a network former.

  70. 70. The formulation of item 69, wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients.

  71. 70. The formulation of item 69, wherein the controlled release carrier system further comprises a plurality of viscosity enhancing agents.

  72. 70. The formulation of item 69, wherein the controlled release carrier system further comprises a plurality of solvents.

  73. 73. The formulation according to item 72, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  74. 64. The formulation of item 63, wherein in vivo release of the opioid analgesic from the controlled release carrier system is substantially free of food effects.

  75. 64. The formulation of item 63, wherein the controlled release carrier system provides enhanced in vivo absorption of the opioid analgesic from the formulation when the formulation is administered with food.

  76. 64. The formulation of item 63, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  77. 77. A formulation according to item 76, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of opioid analgesics from the formulation.

  78. Item 76. The reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of opioid analgesics from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  79. Item 78. The reduced risk of misuse or abuse is further characterized by having no significant effect on the absorption of opioid analgesics from the formulation when the subject takes the formulation and alcohol at the same time. The formulation described.

80. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The oral pharmaceutical preparation is abuse-resistant,
The controlled release carrier system provides controlled in vivo release of the agent characterized in that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent; and The controlled release carrier system comprises HVLCM, a network former, and at least one viscosity enhancer;
The above preparation.

  81. 81. A formulation according to item 80, wherein the active agent is suspended in a controlled release carrier system.

82. Item 81. The formulation of Item 80, wherein each steady state C _min / C _max variation is about 2-3 or less.

  83. 81. The formulation of item 80, suitable for use in a BID dosing regimen.

  84. 81. A formulation according to item 80, wherein the active agent is an opioid.

  85. 81. A formulation according to item 80, wherein the active agent is in salt form.

  86. 81. A formulation according to item 80, wherein the active agent is in the free base form.

  87. 81. The formulation of item 80, wherein the controlled release carrier system further comprises a surfactant.

  88. 81. The formulation of item 80, wherein the controlled release carrier system comprises a plurality of hydrophilic excipients.

  89. 81. The formulation of item 80, wherein the controlled release carrier system further comprises a second viscosity enhancing agent.

  90. 81. The formulation of item 80, wherein the controlled release carrier system comprises a plurality of solvents.

  91. The formulation according to item 90, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  92. 81. The formulation of item 80, wherein in vivo release of the active agent from a controlled release carrier system is substantially free of food effects.

  93. 81. The formulation of item 80, wherein the controlled release carrier system provides enhanced in vivo absorption of the active agent from the formulation when the formulation is administered with food.

  94. 81. The formulation of item 80, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  95. 95. A formulation according to item 94, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  96. 95. The reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  97. 99. The item 96, wherein the reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol simultaneously. Formulation.

98. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The oral pharmaceutical preparation is abuse-resistant,
The controlled release carrier system provides controlled in vivo release of the agent characterized in that the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent; and The respective steady state C _min / C _max variation is about 2-3 or less,
The above preparation.

  99. 99. The formulation of item 98, suitable for use in a BID dosing regimen.

100. 99. The formulation of item 98, wherein the pharmacokinetic in vivo release performance of the active agent from a controlled release carrier system is characterized by a T _max of at least about 4 hours after ingestion by the subject.

  101. 99. A formulation according to item 98, wherein the controlled release carrier system comprises HVLCM, a network former, and at least one viscosity enhancer.

  102. 99. A formulation according to item 98, wherein the active agent is an opioid.

  103. 99. A formulation according to item 98, wherein the active agent is in salt form.

  104. 99. A formulation according to item 98, wherein the active agent is in the free base form.

  105. 102. The formulation of item 101, wherein the controlled release carrier system further comprises a surfactant.

  106. 102. The formulation of item 101, wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients.

  107. 102. The formulation of item 101, wherein the controlled release carrier system further comprises a second viscosity enhancing agent.

  108. 102. The formulation of item 101, wherein the controlled release carrier system further comprises a plurality of solvents.

  109. 109. The formulation of item 108, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  110. 99. A formulation according to item 98, wherein in vivo release of the active agent from a controlled release carrier system is substantially free of food effects.

  111. 99. The formulation of item 98, wherein the controlled release carrier system provides enhanced in vivo absorption of the active agent from the formulation when the formulation is administered with food.

  112. 99. The formulation of item 98, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  113. 113. A formulation according to item 112, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  114. 119. Item 112, wherein the reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  115. 119. Item 114, wherein the reduced risk of misuse or abuse is further characterized by not having any significant effect on absorption of the active agent from the formulation when the subject takes the formulation and alcohol simultaneously. Formulation.

116. An abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The controlled release carrier system comprises HVLCM, a network former, and at least one viscosity enhancer;
The above preparation.

  117. 118. A formulation according to item 116, wherein the viscosity enhancing agent is a synthetic polymer.

  118. 118. A formulation according to item 117, wherein the synthetic polymer is a cellulose derivative.

  119. 118. A formulation according to item 116, wherein the active agent is an opioid.

  120. 117. A formulation according to item 116, wherein the active agent is in salt form.

  121. 117. A formulation according to item 116, wherein the active agent is in the free base form.

  122. 119. The formulation of item 116, wherein the controlled release carrier system further comprises a surfactant.

  123. 119. The formulation of item 116, wherein the controlled release carrier system further comprises a plurality of hydrophilic excipients.

  124. 118. The formulation of item 116, wherein the controlled release carrier system further comprises a second viscosity enhancing agent.

  125. 125. A formulation according to item 124, wherein the second viscosity enhancing agent comprises a stiffening agent.

126. Second viscosity enhancing agent comprises SiO _2, the formulation of claim 125.

  127. 119. The formulation of item 116, wherein the controlled release carrier system further comprises a plurality of solvents.

  128. 128. The formulation according to item 127, wherein the solvent comprises a hydrophobic solvent and a hydrophilic solvent.

  129. 119. Formulation according to item 116, wherein in vivo release of the active agent from a controlled release carrier system is substantially free of food effects.

  130. 119. The formulation of item 116, wherein the controlled release carrier system provides enhanced in vivo absorption of the active agent from the formulation when the formulation is administered with food.

  131. 119. The formulation of item 116, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  132. 134. The formulation of item 131, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  133. 134. The reduced risk of misuse or abuse is characterized by having no significant effect on absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

  134. 140. The item 133, wherein the reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol at the same time. Formulation.

135. An abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
At least 8 hours when the controlled release carrier system is tested on a USP Type II Dissolution Apparatus with a fixed basket assembly using a paddle speed of 100 rpm and a 0.1 N HCl dissolution medium containing a surfactant. Provides for a substantially constant in vitro active agent release of and less than 20% of the active agent from the formulation in a 1 hour in vitro solvent extraction test using EtOH (100 proof) as an extraction solvent at RT Extractable,
The above preparation.

136. An abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
At least 8 hours when the controlled release carrier system is tested on a USP Type II Dissolution Apparatus with a fixed basket assembly using a paddle speed of 100 rpm and a 0.1 N HCl dissolution medium containing a surfactant. Provides a substantially constant in vitro active agent release, and • 30% or less of the active agent can be extracted from the formulation in a 1 hour in vitro solvent extraction test using a group of extraction solvents at RT ,
The above preparation.

137. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The controlled release carrier system comprises HVLCM, a network former, a rheology modifier, and a hydrophilic agent, and the formulation is abuse-resistant,
The above preparation.

  138. 140. The formulation of item 137, wherein the controlled release carrier system further comprises a viscosity enhancing agent.

  139. 139. Formulation according to item 138, wherein the hydrophilic agent also functions as a second viscosity enhancer.

  140. 140. A formulation according to any one of items 137 to 139, wherein the hydrophilic agent is hydroxyethyl cellulose (HEC).

  141. 141. Formulation according to any one of items 137-140, wherein the HVLCM is sucrose acetate isobutyrate (SAIB).

  142. 142. The formulation according to any one of items 137 to 141, further comprising a solvent.

  143. 142. The formulation according to item 142, wherein the solvent is triacetin.

  144. 139. Formulation according to item 138, wherein the viscosity enhancing agent is silicon dioxide.

  145. 144. The formulation according to any one of items 137 to 144, wherein the network-former is cellulose acetate butyrate (CAB).

  146. 146. A formulation according to any one of items 137 to 145, wherein the rheology modifier is isopropyl myristate (IPM).

  147. 147. Formulation according to any one of items 137-146, wherein the active agent is an opioid.

  148. 148. The formulation of item 147, wherein the opioid is oxycodone, oxymorphone, hydrocodone, or hydromorphone.

  149. 150. The formulation according to item 148, wherein the opioid is oxycodone.

  150. 150. Formulation according to any one of items 147 to 149, wherein the opioid is present in free base form.

  151. 150. Formulation according to any one of items 147 to 149, wherein the opioid is present in a salt form.

  152. 152. The formulation of any one of items 137 to 151, further comprising a stabilizer.

  153. 153. The formulation according to item 152, wherein the stabilizer is butylhydroxyl toluene (BHT).

  154. 154. Formulation according to any one of items 137-153, wherein the active agent is micronized.

155. A method for securing and maintaining analgesia in a subject by repeated administration of an oral analgesic formulation,
The preparation is abuse-resistant,
The formulation comprises a controlled release carrier system and an analgesic, and the controlled release carrier system has a steady state C _min / C _max variation within each dose interval that is less than or equal to the therapeutic index of the analgesic Providing controlled in vivo release of an analgesic characterized by
The above method.

156. 164. The method of item 155, wherein each steady state _Cmin / _Cmax variation is about 2-3 or less.

  157. 156. The method of item 155, wherein said repeated administration comprises a BID dosing regimen.

  158. 164. The method of item 155, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  159. 159. The method of item 158, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the analgesic from the formulation.

  160. 159. Item 158, wherein the reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of analgesics from the formulation when the subject takes the formulation and alcohol at the same time. Method.

  161. 158. Item 159, wherein the reduced risk of misuse or abuse is further characterized by having no significant effect on the absorption of analgesics from the formulation when the subject takes the formulation and alcohol simultaneously. the method of.

  162. 164. The method of item 155, wherein in vivo absorption of the analgesic from the formulation is enhanced when the formulation is administered with food.

  163. 164. The method of item 155, wherein the analgesic comprises an opioid.

  164. 164. Method according to item 163, wherein the opioid is present in the formulation as the free base.

165. A method for securing and maintaining analgesia in a subject by repeated administration of an oral analgesic formulation,
The formulation comprises a controlled release carrier system and an analgesic, and further the controlled release carrier system comprises HVLCM, a network former, and at least one viscosity enhancer;
The above method.

  166. 166. Method according to item 165, wherein the formulation is abuse-resistant.

167. Item 165. The controlled release carrier system provides controlled in vivo release of an analgesic, wherein the steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the analgesic The method described.

168. 166. The method of item 167, wherein each steady state _Cmin / _Cmax variation is about 2-3 or less.

  169. 166. The method of item 165, wherein the repeated administration comprises a BID dosing regimen.

  170. 166. The method of item 165, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  171. 171. The method of item 170, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the analgesic from the formulation.

  172. 171. Item 170. The reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of analgesics from the formulation when the subject takes the formulation and alcohol at the same time. Method.

  173. Item 171. The item 171 wherein the reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of analgesics from the formulation when the subject takes the formulation and alcohol at the same time. the method of.

  174. 166. Method according to item 165, wherein in vivo absorption of the analgesic from the formulation is enhanced when the formulation is administered with food.

  175. 166. The method of item 165, wherein the analgesic comprises an opioid.

  176. 174. Method according to item 175, wherein the opioid is present in the formulation as the free base.

  177. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above which releases less than about 2% of the opioid when subjected to extraction into 100 proof ethanol for 5 minutes.

  178. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 2% of the opioid when subjected to extraction into vinegar for 5 minutes.

  179. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 2% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution for 5 minutes.

  180. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 5% of the opioid when subjected to extraction into a cola soft drink for 5 minutes.

  181. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 11% of the opioid when subjected to extraction into 100 proof ethanol for 60 minutes.

  182. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 12% of the opioid when subjected to extraction into vinegar for 60 minutes.

  183. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above wherein less than about 12% of the opioid is released when subjected to extraction into a saturated sodium bicarbonate solution for 60 minutes.

  184. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 22% of the opioid when subjected to extraction into a cola soft drink for 60 minutes.

  185. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above, which releases less than about 5% of the opioid when subjected to extraction into 100 proof ethanol for 5 minutes.

  186. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 5% of the opioid when subjected to extraction into vinegar for 5 minutes.

  187. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 5% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution for 5 minutes.

  188. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 10% of the opioid when subjected to extraction into a cola soft drink for 5 minutes.

  189. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 20% of the opioid when subjected to extraction into 100 proof ethanol for 60 minutes.

  190. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 20% of the opioid when subjected to extraction into vinegar for 60 minutes.

  191. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 20% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution for 60 minutes.

  192. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, wherein the formulation is at room temperature The formulation described above that releases less than about 30% of the opioid when subjected to extraction into a cola soft drink for 60 minutes.

  193. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 11% of the opioid when subjected to extraction in 100 proof ethanol for 5 minutes at 5 minutes.

  194. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 11% of the opioid when subjected to extraction into vinegar for 5 minutes.

  195. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: Wherein the formulation releases less than about 11% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution for 5 minutes.

  196. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: Wherein the formulation releases less than about 30% of the opioid when subjected to extraction into a cola soft drink for 5 minutes.

  197. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 26% of the opioid when subjected to extraction into 100 proof ethanol for 60 minutes at 60.degree.

  198. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 20% of the opioid when subjected to extraction in vinegar for 60 minutes.

  199. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation described above releases less than about 23% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 minutes.

  200. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 45% of the opioid when subjected to extraction into a cola soft drink at 60 minutes.

  201. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 15% of the opioid when subjected to extraction in 100 proof ethanol for 5 minutes at 5 minutes.

  202. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: Wherein the formulation releases less than about 15% of the opioid when subjected to extraction into vinegar for 5 minutes.

  203. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 15% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 5 minutes.

  204. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 45% of the opioid when subjected to extraction into a cola soft drink at 5 minutes.

  205. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 33% of the opioid when subjected to extraction in 100 proof ethanol for 60 minutes at 60.degree.

  206. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The above formulation releases less than about 33% of the opioid when subjected to extraction in vinegar for 60 minutes.

  207. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 33% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 minutes.

  208. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, further comprising: The formulation releases less than about 60% of the opioid when subjected to extraction into a cola soft drink at 60 minutes.

  209. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule; The above formulation that releases less than about 20% of the opioid when subjected to extraction into a group of extraction solvents comprising vinegar, hot tea, saturated sodium bicarbonate, and cola soft drink at 60 ° C. for 60 minutes.

  210. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule; The above formulation that releases less than about 15% of the opioid when subjected to extraction into a group of aqueous buffered extraction solutions in the range of pH 1 to pH 12 at 60 ° C. for 60 minutes.

  211. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule; A group of aqueous extraction solutions that physically break the formulation and each include 60 ° C. water, 25 ° C. water, 60-70 ° C. water, 25 ° C. 0.1 N HCL, and 25 ° C. 100 proof ethanol for 60 minutes each The formulation described above that releases less than about 40% of the opioid when subjected to extraction into.

  212. A controlled release oral pharmaceutical formulation comprising an opioid active agent, wherein the formulation provides effective analgesia to a subject when administered on a twice daily (BID) dosing schedule, and the formulation further comprises a microwave When the formulation was physically disrupted by treatment and then subjected to extraction into a group of aqueous extraction solutions containing water, 0.1 N HCL, and 100 proof ethanol for 60 minutes each at 25 ° C., The formulation, wherein the formulation releases less than about 25% of the opioid.

  213. 213. Formulation according to any one of items 177-212, wherein the opioid is oxycodone, oxymorphone, hydrocodone, or hydromorphone.

  214. The formulation of item 213, wherein the opioid is oxycodone.

  215. 215. A formulation according to any one of items 177 to 214, wherein the opioid is present in free base form.

  216. The formulation according to any one of items 177-214, wherein the opioid is present in a salt form.

217. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The pharmaceutical preparation is abuse-resistant, and the preparation is suitable for twice daily administration (BID),
The above preparation.

  218. An oral pharmaceutical formulation comprising an opioid active agent and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and is formulated for BID administration.

  219. An oral pharmaceutical formulation comprising an opioid active agent and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and provides effective pain relief for at least 12 hours.

  220. 219. Formulation according to any one of items 217 to 219, wherein the active agent is oxycodone, oxymorphone, hydrocodone, or hydromorphone.

  221. The formulation of item 220, wherein the opioid is oxycodone.

  222. 223. Formulation according to any one of items 217-221, wherein the active agent is present in free base form.

  223. 223. Formulation according to any one of items 217-221, wherein the active agent is present in salt form.

  224. 224. A formulation according to any one of items 217 to 223, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.

  225. 224. The formulation of item 224, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of the active agent from the formulation.

  226. 227. Item 224, wherein the reduced risk of misuse or abuse is characterized by having no significant effect on absorption of the active agent from the formulation when the subject takes the formulation and alcohol simultaneously. Formulation.

  227. 227. The item 225, wherein the reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of the active agent from the formulation when the subject takes the formulation and alcohol simultaneously. Formulation.

  228. 227. A formulation according to any one of items 217 to 227, wherein in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food.

  229. An oral pharmaceutical formulation comprising oxycodone and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and is administered on a twice daily (BID) dosing schedule at a 5-day dosing interval. The formulation above, which provides a percent swing (PF) in the range of 85% to 115%.

  230. The formulation of item 229, wherein the PF is in the range of about 95% to 100%.

  231. The formulation according to any of items 229 or 230, wherein the formulation provides effective pain relief for at least 12 hours.

  232. The formulation of any of items 229-231, wherein the formulation is further characterized by having no significant effect on the absorption of oxycodone from the formulation when the subject takes the formulation and alcohol at the same time.

  233. The formulation of any of items 229-232, wherein the formulation is further characterized by low injectability.

  234. 234. A formulation according to any of items 229-233, wherein the formulation is less susceptible to normal abuse forms including injection, inhalation (crushing and nasal inhalation), and volatilization (smoking).

  235. An oral pharmaceutical formulation comprising oxycodone and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and has an abuse index (AQ) value of less than 10 when taken as is with water as intended The said formulation which exhibits.

  236. An oral pharmaceutical formulation comprising oxycodone and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and has an abuse index of less than 30 when taken with 80 proof alcohol after being physically disrupted (AQ) The above preparation exhibiting a value.

  237. An oral pharmaceutical formulation comprising oxycodone and a controlled release carrier system when the pharmaceutical formulation is abuse-resistant and ingested as such and held in the buccal oral cavity for 10 minutes before swallowing The formulation, wherein the formulation exhibits an abuse index (AQ) value of less than about 25.

  238. An oral pharmaceutical formulation comprising oxycodone and a controlled release carrier system, wherein the pharmaceutical formulation is abuse-resistant and has an abuse index (AQ) value of less than 35 when swallowed after ingestion and chewing vigorously. Presenting the above preparation.

  239. 239. A formulation according to either item 235 or 238, wherein the formulation provides effective pain relief for at least 12 hours.

  240. 240. Formulation according to any of items 235-239, wherein the formulation is further characterized by low injectability.

  241. 239. A formulation according to any of items 235-240, wherein the formulation is less susceptible to normal abuse forms including injection, inhalation (crushing and nasal inhalation), and volatilization (smoking).

242. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system, wherein the agent is an opioid, central nervous system (CNS) inhibitor, or CNS stimulant, and the controlled release carrier system is
(A) high viscosity liquid carrier material (HVLCM),
(B) a network-structure-forming agent,
(C) rheology modifier,
(D) a hydrophilic agent, and (e) a solvent,
And HVLCM is sucrose acetate isobutyrate (SAIB), and the network-forming agent is selected from cellulose acetate butyrate (CAB), cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, and cellulose triacetate, The rheology modifier is selected from isopropyl myristate (IPM), caprylic / capric triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate, and benzyl benzoate, and the hydrophilic agent is hydroxyethyl cellulose (HEC), hydroxypropyl Selected from cellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone, and the solvent is triacetin, N-methyl -2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, and is selected from glycofurol, said formulation.

  243. 245. Formulation according to item 242, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone as the free base or as a pharmaceutically acceptable salt thereof.

  244. (A) HVLCM is SAIB, (b) the network-forming agent is CAB, (c) the rheology modifier is IPM, (d) the hydrophilic agent is HEC, and (e) the solvent is triacetin. The formulation of item 243, wherein

  245. (A) 1.3-35 wt% pharmacologically active agent, (b) 2-10 wt% network-forming agent, (c) 0.1-20 wt% rheology modifier, (d) 1-8 wt 251. Formulation according to any one of items 242-244, comprising:% hydrophilic agent, (e) 10-40 wt% solvent, and (f) 30-60 wt% HVLCM.

  246. 264. The formulation of any one of items 242-245, wherein the controlled release carrier system further comprises a viscosity enhancing agent.

  247. 249. The formulation according to item 246, wherein the viscosity enhancing agent is silicon dioxide.

  248. 249. Formulation according to any one of items 242-247, further comprising a stabilizer.

  249. 249. Formulation according to item 248, wherein the stabilizer is butylhydroxyl toluene (BHT).

  250. When the formulation was tested on a modified USP Type II Dissolution Apparatus with a stainless steel stationary basket assembly using a paddle speed of 100 rpm and a 0.1 N HCI dissolution medium containing 0.5% sodium lauryl sulfate. Provides substantially constant in vitro active agent release for at least 8 hours and less than 20% of the active agent from the formulation after 1 hour at ambient temperature using EtOH (100 proof) as the extraction solvent 249. The formulation according to any one of items 242-249, which is extracted.

  251. Less than 20% of the active agent is extracted after 60 minutes extraction into EtOH (100 proof) at ambient temperature and less than 30% after 60 minutes extraction into EtOH (100 proof) at 60 ° C. , The formulation according to any one of items 242-250.

  252. 264. Formulation according to any one of items 242-251, wherein the formulation of active agent and carrier system is encapsulated in a biodegradable capsule.

  253. 253. The formulation of item 252, wherein the capsule comprises gelatin, hydroxyethylcellulose, or hydroxypropylmethylcellulose.

  254. 253. Formulation according to item 251 or 252, wherein the capsule is packaged in a single dose blister or a multi-dose plastic bottle.

255. A process for preparing an oral pharmaceutical formulation as defined in item 242, comprising:
(I) preheating the HVLCM;
(Ii) mixing the solvent with preheated HVLCM to form a homogeneous solution of HVLCM in the solvent;
(Iii) dissolving the network former in the solution by dispersing the network former in the solution;
(Iv) mixing a solution of 5-30% of the rheology modifier, or optionally 5-30% of the stabilizer and the rheology modifier, with the formulation obtained in step (iii);
(V) mixing a pharmacologically active agent with the formulation obtained in step (iv);
(Vi) mixing a hydrophilic agent with the formulation obtained in step (v);
(Vii) optionally mixing a viscosity enhancing agent with the formulation obtained in step (vi);
(Viii) mixing the remaining part of the rheology modifier with the formulation obtained in step (vi) or, if step (vii) is performed, with the formulation obtained in step (vii). When,
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

256. A process for preparing an oral pharmaceutical formulation as defined in item 242, comprising:
(I) preheating the HVLCM;
(Ii) mixing the solvent with preheated HVLCM to form a homogeneous solution of HVLCM in the solvent;
(Iii) optionally mixing a solution of stabilizer and 5-30% of the rheology modifier with the solution obtained in step (ii);
(Iv) mixing the rheology modifier or, if step (iii) is performed, mixing the remaining part of the rheology modifier with the solution obtained in step (ii) or (iii);
(V) optionally mixing a viscosity enhancer with the formulation obtained in step (iv);
(Vi) In the solution by dispersing the network-forming agent in the solution obtained in step (iv) or, if step (v) is performed, in the solution obtained in step (v). Dissolving the network-forming agent in
(Vii) mixing a pharmacologically active agent with the formulation obtained in step (vi);
(Viii) mixing a hydrophilic agent with the formulation obtained in step (vii);
(Ix) optionally filling the capsule with the formulation obtained in step (viii);
(X) optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles;
Including the above process.

  257. An oral pharmaceutical preparation obtainable by the process defined in item 255 or 256.

1 illustrates a laboratory scale manufacturing process (Process Schemes 1-3) described in Example 1. 1 illustrates a laboratory scale manufacturing process (Process Schemes 1-3) described in Example 1. 1 illustrates a laboratory scale manufacturing process (Process Schemes 1-3) described in Example 1. 2 shows the GMP manufacturing process (Process Scheme 6) described in Example 1a. 2 shows the GMP manufacturing process (Process Scheme 7) described in Example 1b. 2 shows the GMP manufacturing process (Process Schemes 8 and 9) described in Example 1c. 2 shows the GMP manufacturing process (Process Schemes 8 and 9) described in Example 1c. FIG. 4 shows a commercial scale manufacturing process (Process Schemes 4-5) as described in Example 2. FIG. FIG. 4 is a pictorial diagram of a modified dissolution tank and paddle described in Example 3. Figure 2 shows the in vitro release performance of test capsules with 10, 20, and 40 mg content as described in Example 3a. Figure 3 shows the results of an in vitro dissolution test of a 5 mg content test capsule described in Example 3b. Figure 3 shows the results of an in vitro dissolution test of a 5 mg content test capsule described in Example 3b. Figure 3 shows the results of an in vitro dissolution test of a 5 mg content test capsule described in Example 3b. FIG. 4 shows the results of an in vitro dissolution test of a 20 mg content test capsule described in Example 3b. FIG. FIG. 4 shows the results of an in vitro dissolution test of a 20 mg content test capsule described in Example 3b. FIG. FIG. 4 shows the results of an in vitro dissolution test of a 20 mg content test capsule described in Example 3b. FIG. FIG. 4 shows the results of an in vitro dissolution test of a 40 mg content test capsule described in Example 3b. FIG. FIG. 4 shows the results of an in vitro dissolution test of a 40 mg content test capsule described in Example 3b. FIG. FIG. 4 shows the results of an in vitro dissolution test of a 40 mg content test capsule described in Example 3b. FIG. FIG. 6 shows the average dissolution data results of the in vitro dissolution test of the HMH test capsule described in Example 3d. FIG. 5 shows the average dissolution data results of the in vitro dissolution test of the HCB1 and HCB2 test capsules described in Example 3e. FIG. 5 shows the average dissolution data results of the in vitro dissolution test of the HCB1 and HCB2 test capsules described in Example 3e. FIG. 6 shows the average dissolution data results of the in vitro dissolution test of the OMH1-OMH10 test capsules described in Example 3f. FIG. 6 shows the average dissolution data results of the in vitro dissolution test of the OMH1-OMH10 test capsules described in Example 3f. FIG. 6 shows the average dissolution data results of the in vitro dissolution test of the AMP1-AMP3 test capsules described in Example 3g. FIG. 5 shows the average dissolution data results of the in vitro dissolution test of the MPH1-MPH6 test capsules described in Example 3h. FIG. 5 shows the average dissolution data results of the in vitro dissolution test of the MPH1-MPH6 test capsules described in Example 3h. FIG. 4 shows the overall kinetic behavior of active agent extraction from test capsules and control tablets into a group of household solvents at ambient temperature (RT) in the in vitro abuse resistance test described in Example 4a. FIG. 4 shows the overall kinetic behavior of active agent extraction from test capsules and control tablets in a group of household solvents at high temperature (60 ° C.) in the in vitro abuse resistance test described in Example 4a. Shows the results extracted from the test capsules in a group of household solvents (vinegar, coal soft drink, hot tea, and saturated sodium bicarbonate solution) compared to the SR control, as described in Example 4b It was obtained in an in vitro abuse resistance test. The results of extraction from a test capsule into a group of aqueous buffers (pH 1 to pH 12) compared to the SR control are shown and were obtained in the in vitro abuse resistance test described in Example 4b. Shows the extraction results when the test capsules were physically broken compared to the physically broken SR control and then extracted into a group of household solvents (hot and cold water, strong acid, and 100 proof ethanol). And obtained in the in vitro abuse resistance test described in Example 4b. Shows the extraction results of microwave treatment of the test capsules compared to the SR control, followed by extraction into a group of household solvents (water, strong acid, and 100 proof ethanol), as described in Example 4b. It was obtained in an abuse resistance test. The volatilization results of the test capsules are shown in contrast to the SR control and were obtained in the in vitro abuse resistance test described in Example 4d. FIG. 2 shows the mean linear plasma concentration-time curve of the active agent in the clinical trial described in Example 7a. FIG. 4 shows the mean linear plasma concentration-time curve of the active agent in the clinical trial described in Example 7b. FIG. 5 shows the mean linear plasma concentration-time curve of the active agent in the clinical trial described in Example 7c. The results of the dose proportionality test of test capsules containing oxycodone in 5, 10, 20, and 40 mg doses (dosage strenghts) are shown and obtained in the clinical study described in Example 7c. Figure 8 shows the results of an in vivo abuse resistance test comparing SR control tablets containing 10 mg oxycodone with an immediate release oxycodone formulation as described in Example 8. Figure 8 shows the results of an in vivo abuse resistance test comparing SR control tablets containing 10 mg oxycodone with an immediate release oxycodone formulation as described in Example 8. FIG. 9 shows the mean linear plasma concentration-time curve of the active agent in the clinical trial described in Example 8. FIG. FIG. 9 shows the results of an in vivo abuse resistance test comparing 40 mg test capsules with 40 mg oxycodone-containing SR control tablets and immediate release oxycodone formulations as described in Example 8a. FIG. 9 shows the results of an in vivo abuse resistance test comparing 40 mg test capsules with 40 mg oxycodone-containing SR control tablets and immediate release oxycodone formulations as described in Example 8a. FIG. 5 shows the results of an in vivo abuse resistance test of a 40 mg test capsule containing oxycodone after being held in the buccal oral cavity as described in Example 8b. FIG. 9 shows the results of an in vivo abuse resistance test of an oxycodone-containing 40 mg test capsule taken either as whole or after chewing vigorously as described in Example 8c. FIG. 4 shows the mean linear plasma concentration-time curve of the active agent in the in vivo abuse tolerance test described in Example 8d. Shown is the mean plasma concentration of oxycodone after ingestion (0-6 hours) of an oxycodone-containing 40 mg test capsule when ingested with water or with 4%, 20%, or 40% ethanol as described in Example 8d. ing. FIG. 2 shows the mean linear plasma concentration-time curve of amphetamine for test capsules administered in the clinical trial described in Example 11. FIG. The chemical structure of sucrose acetate isobutyrate (SAIB) is shown.

  Before describing the present invention in detail, it should be understood that the present invention is not limited to the specifically exemplified support materials or process parameters. Of course, they can be changed. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the present invention only and is not intended to be limiting. .

  All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety, both above and below.

  As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the content clearly differs. It must be noted. Thus, for example, reference to “a non-polymeric support material” includes a mixture of two or more such support materials, and reference to “solvent” includes two or more such solvents. Where mixtures are included and “active agents” are referred to, mixtures of two or more such agents are included, and so on.

  Our previous US patent application, US Patent Application Publication No. 2004/0161382 (hereinafter referred to as “382 Publication”), entitled “Oral Drug Delivery System”, contains oral pharmacologically active agents. Pharmaceutical formulations and drug delivery devices suitable for delivery are described. This novel formulation and device is characterized by a unique combination of pharmaceutical excipients comprising HVLCM, a network former, and optionally rheology modifiers and / or solvents, Thus, a controlled release carrier system is provided. The controlled release carrier system is filled with the active agent of interest. The system will also release the active agent over a period of time in an aqueous environment, particularly in an environment similar to that of a mammalian GI tract. The controlled release carrier system further provides the added benefit of enhanced abuse resistance. In this case, the carrier system utilizes substantially all or most of the sequestered active agent in an immediate release form that can be ingested, inhaled, or injected to provide the euphoric effect of the system. A variety of physical disruption and other in vitro extraction techniques (eg, extraction in ethanol, water, or other common solvents) that may be utilized by those wishing to override Resistant to Thus, the 382 publication describes several controlled release carrier systems that can be used to produce oral formulations or oral delivery devices that provide desirable controlled release kinetic behavior and / or abuse resistance properties. .

The main object of the present invention is to provide improved pharmaceutical formulations and drug delivery devices suitable for oral delivery of pharmacologically active agents. However, such improved formulations and delivery devices are based on the controlled release carrier system described in publication 382. In this regard, a control that provides all of the benefits of those described in publication 382 and further provides enhanced safety properties and / or abuse resistance in addition to enhanced in vivo pharmacological performance. There remains a need in the art to provide releasable carrier systems. One of the major obstacles faced by those skilled in the art who desire to provide such a controlled release carrier system is exactly due to the nature of the carrier system itself. More specifically, unique controlled release carrier systems are responsible for in vivo pharmacological performance. In this case, the active agent must be delivered from the system by diffusion from the system as it passes through the GI tract. The controlled release carrier systems described above are also involved in in vitro abuse resistance performance and in vivo safety performance. That is, the carrier system must prevent the active agent from being released from the system when contacted with a highly efficient aqueous solvent and / or when exposed to an aqueous environment having a low or high pH for an extended period of time. Thus, for example, to increase overall delivery efficiency (AUC) or to provide a prolonged release rate (an operation designed to increase the release of active agent from a controlled release carrier system). The operations that can be performed on the system will typically compromise the in vitro abuse resistance and in vivo safety performance of the system described above. This is because formulation manipulations that increase C _max or decrease T _max generally allow for higher volume / faster extraction and thus can impair abuse resistance (eg, in Changes planned to increase the rate / degree of in vivo drug release also increase the rate / degree of in vitro drug release if an attempt is made to invalidate the controlled release mechanism of the formulation). The term “AUC” is a curve obtained from an in vivo assay in a subject by plotting the plasma concentration of the active agent in the subject against the time measured from the time of administration to the time “T” after administration. It means the bottom area. Time T will correspond to the delivery time of the active agent to the subject. Similarly, operations that can be performed on a controlled release system to enhance in vitro abuse resistance performance and in vivo safety performance (operations designed to reduce the release of active agent from a controlled release carrier system) are: Typically, it will impair the in vivo pharmacological performance of the systems described above. As used throughout this specification and the appended claims, the term “abuse resistance” is fully interchangeable with the related terms “abuse deterrence”, as well as “tamper resistance” and “extraction resistance”. Therefore, it means the exact same thing.

Accordingly, in one aspect of the invention, an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent in a controlled release carrier system is provided. The subject formulation provides controlled in vivo release of the agent wherein the controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the subject active agent It is characterized by doing. "Abuse resistance" means herein that the formulation is resistant to extraction into ethanol (80 or 100 proof). For example, after 60 minutes extraction into 100 proof ethanol at ambient temperature (RT), less than about 20%, preferably less than about 15%, more preferably less than about 10-11% of the active agent is extracted at 60 ° C. Less than about 30%, more preferably less than about 28%, more preferably less than about 25-27% of the active agent after extraction for 60 minutes in 100 proof ethanol at 80 proof at ambient temperature (RT) Less than about 20%, preferably less than about 15%, more preferably less than about 12-13% of the active agent is extracted after 60 minutes of extraction in ethanol and in 80 proof ethanol at ambient temperature (RT) After 180 minutes of extraction, less than about 40%, preferably less than about 35%, more preferably less than about 30-32% of the active agent is extracted. The term “ambient temperature” used herein interchangeably with “room temperature” and / or “RT” means the normal temperature of the working area or laboratory and is in the range of about 18-25 ° C. , And more specifically used herein to represent a normal temperature of 25 ° C. In vitro test methods, techniques, equipment, and fixtures suitable for determining if a formulation is properly resistant to extraction into ethanol are described in Example 4 below.

  In certain preferred embodiments, the “abuse-resistant” formulation is also resistant to extraction into a group of common household solvents. That is, the formulation is further resistant to one or more of the following extractions. (A) Resistant to extraction into cola soft drink (pH about 2.5) and consequently less than 30% of active agent after 60 minutes extraction into cola soda at ambient temperature (RT) Preferably less than about 25%, more preferably less than about 22-23%, and / or less than about 50%, preferably less than about 48% after 60 minutes of extraction into cola soda at 60 ° C. Preferably less than about 42-46% is extracted. (B) resistant to extraction into household vinegar (pH about 2.5), resulting in less than 20% of active agent after 60 minutes extraction into vinegar at ambient temperature (RT), Preferably less than about 15%, more preferably less than about 11-13% are extracted and / or less than about 25%, preferably less than about 23%, more preferably after extraction into vinegar at 60 ° C. for 60 minutes. About 18-21% is extracted. Or (c) resistant to extraction into a saturated sodium bicarbonate solution (pH about 8.5), resulting in 20% of the active agent after 60 minutes extraction into a saturated sodium bicarbonate solution at ambient temperature (RT). %, Preferably less than about 15%, more preferably less than about 10-14% and / or less than about 27% of the active agent after extraction for 60 minutes in a saturated sodium bicarbonate solution at 60 ° C., preferably Less than about 25%, more preferably less than about 20-24% is extracted. Again, an in vitro test suitable to determine if the formulation is adequately resistant to extraction into these additional household solvents is described in Example 4 below. .

In certain other preferred embodiments, “abuse-resistant” formulations are also characterized by having low injectability. The injectability of the formulation can be assessed using standard test methods, specifically using the test method described in Example 4c below, in which case the “syringe inhalability” of the test formulation and Both “injectability” are determined. In this context, the properties of an injectable suspension are defined as syringe inhalation and injectability. Syringe inhalation is related to the ability to draw a suspension into an empty syringe through a hypodermic needle, while injectability is directed to the ability to push the suspension out of a filled syringe through the hypodermic needle. Both properties depend on the viscosity and physical properties of the test formulation. A formulation or formulation comprising the formulation will have a “low injectability” if the formulation has low syringe inhalation and / or injectability. In related embodiments, “abuse-resistant” formulations are also characterized by being less susceptible to the usual forms of abuse including injection, inhalation (crushing and nasal inhalation), and volatilization (smoking). Standard tests for assessing the sensitivity of particular formulations to these abuse forms are known in the art and examples include the tests described in Examples 4 and 8 below. In other further related embodiments, the “abuse-resistant” formulation also has an abuse index (AQ) value of less than 10 when taken with water as intended, 80 proof alcohol after physical disruption AQ value of less than 30 when ingested together, AQ value of less than about 25 when ingested and kept swallowed in the buccal cavity for 10 minutes, and / or swallowing after ingesting and chewing vigorously Is characterized by having an AQ value of less than 35. Abuse index (AQ) can be used as a way to express the attractiveness of a formulation / formulation to abuse. AQ takes into account the observation that increasing C _max and decreasing T _max increases the attractiveness of certain formulations to abuse. It is expressed as the equation AQ = C _max / T _max . AQ is a dose-dependent metric when C _max varies with dose. The AQ of any formulation under normal or abuse conditions can be assessed using standard test methods known to those skilled in the art, examples include the test methods described in Example 8 below. .

“Providing controlled in vivo release of an agent characterized by a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent” means herein steady state Thus, a controlled release carrier system means that an optimal therapy is provided in a therapeutic method using repeated administration of a formulation according to the invention. “Dose interval” means the period between a single dose of a formulation and subsequent doses in a repeated dose regimen (eg, when administered every 24 hours (QD), the dose interval is 24 times between doses). And if administered every 12 hours (BID), there will be 12 hours between doses). In this context, in order to evaluate the optimal administration of a particular active agent in a subject, the “therapeutic index” is the plasma concentration (systemic concentration) so that the therapeutic index is equal to the ratio C ^* _max / C ^* _min. Can be defined. Here, “C ^* _max ” and “C ^* _min ” are the maximum and minimum desired plasma concentrations, respectively. That is, the active agent will have a toxic effect above the maximum desired plasma concentration point, and below the minimum desired plasma concentration point, the active agent no longer provides the desired pharmacological effect. Will. See Theeuwes et al. (1977) Journal of Pharmaceutical Sciences 66 (10): 1388-1392. These maximum and minimum plasma concentration ranges are, of course, related to repeated dose doses, where the effective dose is generally an effective AUC (at steady state). The therapeutic index for any particular active agent of interest can be readily ascertained by one skilled in the art. Of course, the therapeutic index can vary from person to person, and in some, it can change over time as disease progression or conditions of treatment change. In general, in the case of opioids, patients become more resistant to drugs as the level of pain increases and higher doses are required. The physician will therefore adjust the dose over time. However, a consistent and reproducible rocking index = C _max / C _min so that only the dose that gives the mean plasma level or AUC at steady state is needed to achieve optimal therapy. It is highly desirable to have a formulation with

In the formulations according to the present invention, the controlled release carrier system has a variation (ratio of maximum and minimum plasma concentration extremes (C _max and C _min ) measured at steady state when administered at a therapeutically effective dose. ), That is, providing consistent and reproducible controlled release of the active agent such that each steady state C _min / C _max variation is below the therapeutic index of that particular active agent. In some cases, steady state C _min / C _max variation within each dosing interval is particularly low. That is, it is about 2 to 3 or less. In a preferred embodiment, the steady state C _min / C _max variation within each dosing interval is about 2 or less. In other cases, for example, if the therapeutic index of the active agent is substantially greater, the steady state C _min / C _max variation within each dosing interval may be greater, eg, about 5-6, It may be more than that. However, the release from the formulations according to the invention is preferably fairly well controlled, providing a particularly low variation regardless of the size of the therapeutic index. The ability of a controlled release carrier system to provide controlled in vivo release of an agent, characterized in that steady state C _min / C _max variation within each dosing interval is less than or equal to the therapeutic index of the active agent is known to those skilled in the art. For example, a standard in vitro dissolution test, specifically using the in vitro dissolution method shown in Example 4 below, and then applying the IVIVC conversion function as shown in Example 6 below, Can be readily determined by determining the expected in vivo variability over the duration of the controlled release. In addition to these in vitro test methods, controlled release properties that provide controlled in vivo release of agents characterized in that steady state C _min / C _max variation within each dosing interval is below the therapeutic index of the active agent The ability of the carrier system can be readily determined by those skilled in the art by using standard in vivo pharmacological test methods such as those described in Examples 7 and 9-11 below.

As another option, the controlled release carrier system according to the present invention can provide consistent and reproducible controlled release of the active agent characterized by having a low degree of rocking at steady state. Thus, in certain preferred embodiments of the present invention, the abuse-resistant oral pharmaceutical formulation according to the present invention has a BID (twice a day), for example, over a dosing interval (eg 5 days) sufficient to achieve a steady state. Enhanced in vivo pharmacokinetics such that the percent swing (PF) is in the range of about 85% to 115%, preferably about 95% to 100% when the formulation is administered continuously on the dosing schedule. Controlled release carrier systems that provide biological performance. PF values can be obtained using standard pharmacokinetic analysis of plasma concentration / time data obtained in a steady state test format. Here, PF = 100 × (C _min −C _max ) / C _average = 100 × (C _min −C _max ) / (AUC _0−τ / τ (where τ = time)) “C _max ” and Means the maximum concentration of the active agent in the subject's plasma and is generally expressed in units per mass, typically nanograms per milliliter, “C _min ” means activity in the subject's plasma Refers to the minimum concentration of an agent, generally expressed in unit volume by mass, typically in milliliters per nanogram AUC _0-τ is the plasma concentration over time = 0 to the dosing interval (τ) − The area under the time curve, calculated using the linear trapezoidal formula.

  In certain other preferred embodiments of the invention, the abuse-resistant oral pharmaceutical formulation comprises a controlled release carrier system that can provide enhanced in vivo pharmacokinetic performance, and as a result, from the carrier system. In vivo release of the active agent is substantially unaffected by the food effect, or the carrier system actually enhances in vivo absorption of the active agent from the carrier system when administered in the presence of food. Receives a food effect. In this context, the physiological behavior of the stomach is usually determined by whether it contains food (fed state) or is empty (fast state). In the fed state, food undergoes mixing and partial digestion in the distal stomach as the stomach contracts, thereby facilitating transfer of material to the main part of the stomach for further digestion. At the end of the digestive phase, the stomach enters a fasting phase and begins a cycle called the interdigestive myoelectric cycle. These changes in physiological behavior, as well as certain attendant chemical changes (eg, pH) as the stomach switches between fed and fasted states, cause the rate of delivery of the active agent from the oral formulation and / or Or it may cause fluctuations in quantity. More specifically, various formulation-dependent food-induced absorption changes (hereinafter “food effects”) can occur when using controlled release compositions. These changes include a decrease in rate and / or extent when consumed in the fed or fasted state, an increase in rate and / or extent, and a difference in absorption when the composition is consumed with a low or high fat diet. Irregular or variable absorption of the active agent from a controlled release composition such as In extreme cases, the controlled release composition may have a significant food effect and consequently ingest the composition with food or with various types of food (high fat vs. low fat) A significant increase in absorption (dose dumping) can occur, so the formulation may be unsafe with very potent active agents and / or active agents with potential for significant side effects . In such cases, i.e., if the formulation exhibits a significant food effect, medications according to dietary intake may be listed as part of the product label to ensure consistent and safe absorption. A formulation is characterized as having a food effect if there is a significant difference in both the rate and extent of absorption of the active agent from the oral formulation when administered in the fed vs fasted state. In some cases, the formulation may have a food effect where administration of the formulation with food enhances the bioavailability of the active agent. On the other hand, if there is no significant difference in both the rate and extent of absorption of the active agent from the oral formulation as compared to the fed state and the fasted state, the formulation is characterized as having substantially no food effect. (Still, for example, co-administration with food can affect the maximum plasma concentration of the active agent).

The controlled release carrier system according to the present invention has a food effect (administering the formulation with food will significantly affect both the rate and extent of absorption of the active agent, ie the rate of absorption is It will be reduced and the extent of absorption will be increased), as both having a consistent food effect (administering the formulation with food will significantly affect both the rate and extent of absorption of the active agent). However, there is no significant difference or variability in this food effect when contrasting various types of meals or diets) or as a product that is substantially unaffected (with or without food) Both the rate at which the maximum plasma concentration of the active agent is reached, ie, T _max, and the degree of absorption, ie, AUC, are not significantly affected, but are still Administration can be provided as characterized (which can affect the maximum plasma concentration or C _max of the active agent). Thus, as used herein, “absence of food effect” means that the ratio of mean AUC at feeding / mean AUC at fasting is 80% to the acceptable bioequivalence limit for pharmaceutical formulations. Meaning that it is within the range of 125%, and the ratio of mean _Tmax / fasting average _Tmax is also within the acceptable bioequivalence limit of 80% to 125%. In addition, as used herein, “enhanced in vivo absorption” means that the ratio of average fed AUC / average fasted AUC exceeds at least the bioequivalence upper limit of 125%, and Mean ratio of fed mean T _max / fasted mean T _max exceeds the bioequivalence upper limit of 125%. As used herein, “consistent food effect” means that there is enhanced in vivo absorption and the ratio of high fat average AUC / low fat average AUC is the drug A bioequivalence limit of 80 that is within the acceptable bioequivalence limit of 80% to 125% for the formulation and the mean T _max / fasting average T _max is also acceptable. It means that it exists in the range of% -125%. “C” means the concentration of the active agent in the plasma of a subject and is generally expressed in units per mass, typically in nanograms per milliliter. “C _max ” means the maximum concentration of an active agent in a subject's plasma within a specified time interval “T” or “T _max ” after administering the active agent to a subject, typically per mass Expressed in unit volume, typically nanograms per milliliter. As used herein, “fasting” refers to fasting for at least 10 hours overnight in a clinical trial setting, an additional 4 hours after dose administration, and then a standard high fat diet ( It means that the preparation is administered to a subject who has ingested breakfast. As used herein, “feeding” means that the formulation is administered to a subject immediately after ingesting a high-fat or low-fat standard diet under clinical trial conditions. The “high fat” standard meal consists of 2 toasted white breads with butter, 2 baked buttered eggs, 2 bacon, 2 oz hash brown potatoes, and 8 oz whole milk (about 33 g Protein, 58-75 g fat, 58 g carbohydrate, 870-1020 calories). The “low fat” standard diet consists of a toasted white bread with butter or jelly, 1 oz dry cereal (corn flakes), 8 oz skim milk, 6 oz orange juice, and a banana (approximately 17 g protein, 8 g fat, 103 g carbohydrates, 583 calories). All of the pharmacokinetic values described above can be readily determined by those skilled in the art using established in vivo clinical follow-up procedures as described in Example 7 below. See also "Guidance for Industry", Food-Effect Bioavailability and Fed Bioequivalence Studies, US Dept Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER), December 2002.

Accordingly, in a particularly preferred embodiment of the invention, an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system is provided. The controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent, and in vivo release of the active agent from the controlled release carrier system has a substantial food effect. Providing controlled in vivo release of the agent, characterized in that In one aspect of the invention, the pharmacologically active agent is present in the formulation as a salt. In another aspect of the invention, the active agent is an opioid salt. In another particularly preferred embodiment of the invention, an abuse-resistant oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system is provided. The controlled release carrier system has a steady state C _min / C _max variation within each dosing interval that is less than or equal to the therapeutic index of the active agent, and the extent of in vivo absorption of the active agent from the controlled release carrier system is with the food Provide controlled in vivo release of an agent characterized by being enhanced when the formulation is administered. In one aspect of the invention, the formulation is characterized as having a consistent food effect, and as a result, the degree of in vivo absorption of the active agent from the controlled release carrier system is determined by administering the formulation with food. However, there is no significant difference between various diets or dietary intakes (high fat and low fat eating states). In this regard, this particular embodiment of the present invention is considered to be a safer and more effective formulation. Because the bioavailability of the active agent from the formulation is enhanced by the food effect, this food effect is nevertheless consistent with a series of reasonable diets and actually ingested. This is because the dose is not dose damped when administered simultaneously with a greasy high fat diet that is less sensitive to certain foods. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can include opioids, amphetamines, or methylphenidates, in either case as either a salt or a free base. In one aspect of the invention, the active agent is an opioid free base, specifically oxycodone free base.

The ability to manipulate controlled release carrier systems made in accordance with the present invention to provide various food effect performance was evaluated as follows. Exemplary composed of 40.1 wt% SAIB, 29.7 wt% triacetin, 17 wt% IPM, 6 wt% HEC, 5.25 wt% CAB, 2 wt% SiO ₂ , and 0.02 wt% BHT A controlled release formulation was prepared and filled into size 00 gelatin capsules. Using a modified USP Type II dissolution apparatus, a paddle speed of 100 rpm, a temperature controlled to 37 ° C., and a dissolution medium consisting of 0.1 N HCl and 0.5% SDS, the dissolution test (Examples below) Method 3) of 3 was constructed. Sample formulations were added and the whole mass was removed at 3, 6, 8, 10, 12, 18, 24, and 36 hours. Changes in sample morphology and weight were examined to assess water entry into the formulation over time (n = 2). It was found that there was a significant weight change as a function of time. In this case, a significant weight loss was observed over the first 6 hours, followed by a weight gain in 8-10 hours. Next, the outflow of the solvent (triacetin) was evaluated over time. As a result of testing with dissolution media samples taken over time using the same test parameters, elution of triacetin occurred within the first 3 hours, during which time water uptake into the formulation was slow It has been suggested. However, after the 3 hour time point, water uptake is significantly increased. These results suggest that factors such as the solubility of the active agent in the selected solvent and in water can affect the kinetic behavior of the release of the agent from the formulation. In this case, the active agent with high solubility in solvent and low solubility in water has a rapid onset of release (eg burst) in the first 6-8 hours of delivery, followed by a steady state of release or release in about 12 hours. An active agent that is expected to exhibit a tapering state while having high solubility in water and low solubility in solvent will follow a zero order dissolution profile (substantially constant) over delivery time. To evaluate this expectation, oxycodone free base (high solubility in triacetin, low solubility in water) and salt form oxycodone (low solubility in HCl, triacetin, high water) using sample controlled release formulations Oral formulations containing (solubility) were prepared and exemplary formulations were evaluated using the dissolution test methods described above. The results of the test demonstrated that the formulation containing the active agent in the free base form showed strong initial release performance, with approximately 60-70% of the total active agent being released within the first 12 hours. . In contrast, formulations containing the salt form of the active agent show a substantially constant release performance over the entire test duration, the onset of action is much slower, and about 20-30 of the total active agent. % Were released within the first 12 hours. Therefore, matching the active agent solubility parameter with the components of the controlled release formulation will speed up or delay the onset of action and increase or decrease the total amount of active agent absorbed from the formulation over the dosing interval. It is possible.

In certain other preferred embodiments of the invention, the abuse-resistant oral pharmaceutical formulation comprises a controlled release carrier system that can provide enhanced in vivo pharmacokinetic performance, eg, an active agent from the carrier system. In vivo release is sufficient to provide a steady state C _min / C _max variation that is about 2 or 3 or less. “Steady state” means a state in which the amount of active agent present in the plasma of a subject does not change significantly over a long period of time. “C” means the concentration of the active agent in the plasma of a subject and is generally expressed in units per mass, typically in nanograms per milliliter. “C _max ” means the maximum concentration of an active agent in a subject's plasma within a specified time interval “T” or “T _max ” after administering the active agent to a subject, typically per mass Expressed in unit volume, typically nanograms per milliliter. “C _min ” means the minimum concentration of a drug in a subject's plasma within a specified time interval after administration of the active agent to the subject, generally in units of mass per volume, typically per nanogram Expressed in milliliters. Again, each of these pharmacokinetic values can be readily determined by one of ordinary skill in the art using established in vivo clinical follow-up procedures as described in Example 7 below. .

In another further preferred embodiment of the invention, the abuse-resistant oral pharmaceutical formulation comprises a controlled release carrier system that can provide enhanced in vivo pharmacokinetic performance, eg, an opioid analgesic from the carrier system. In vivo release is characterized by a T _max of at least about 4 hours after ingestion by the subject. In one aspect of the invention, the opioid analgesic is present in the formulation as the free base. In another aspect of the invention, the opioid analgesic active is free base form of oxycodone. This enhanced in vivo pharmacokinetic performance can be readily assessed by those skilled in the art using established in vivo clinical trial procedures as described in Example 7 below.

  In certain other preferred embodiments of the invention, the abuse-resistant oral pharmaceutical formulation comprises a controlled release carrier system that can provide a reduced risk of misuse or abuse. An important advantage of the formulations disclosed herein is that they have abuse-resistant properties and / or reduced risk of diversion. In this context, the formulations contained within the formulation (controlled release carrier system and active agent) are not susceptible to conventional crushing, pulverization, or milling techniques, and are not conventional, such as ethanol. Less susceptible to extraction using household solvents. In addition, the formulations contained within the formulation (controlled release carrier system and active agent) also have the effect of conventional heat extraction techniques (eg, microwave treatment), vaporization techniques (eg, volatilization or smoking). Less susceptible to injection techniques due to the inadequate syringe inhalation and / or injectability of the formulation. Specifically, because HVLCM is a highly viscous liquid, formulations containing HVLCM avoid the possibility of crushing for inhalation purposes. However, in certain embodiments of the present invention, the controlled release carrier system can further provide enhanced safety properties. In this regard, the subject formulation is characterized as having one or both of the following enhanced safety characteristics. That is, a controlled release carrier system is characterized by a low in vitro solvent extraction rate of the active agent from the formulation, and / or the carrier system is or is intended when a subject simultaneously ingests the formulation with ethanol. Instead of swallowing the entire preparation, it is characterized by having no significant effect on the absorption of the active agent from the preparation when the tablet is chewed (chewed) or held in the mouth (buccal mouth). This second property, so-called “dose dumping”, is a major concern for supervisors involved in the safety of powerful analgesics such as opioids. Because, unlike standard concerns regarding intentional abuse, patients may inadvertently take a controlled release formulation containing a potent opioid with a glass of wine or cocktail, or children may Because they could find the dropped capsule and crush it. If this action is sufficient to disable the controlled release system, a potentially lethal dose of an opioid analgesic can be inadvertently administered. In this regard, recently, the Palladone® brand controlled release hydromorphone formulation was recovered from the US market because of this safety.

Accordingly, certain particularly preferred embodiments of the present invention provide an abuse-resistant oral pharmaceutical formulation comprising a controlled release carrier system that can provide a reduced risk of misuse or abuse. However, the carrier system is characterized by having no significant effect on the absorption of the pharmacologically active agent from the formulation when the subject simultaneously ingests the formulation with ethanol. The ability of a formulation to avoid this dose-dumping effect can be assessed using a carefully controlled in vivo human clinical test method as described in Example 8 below. “No significant effect” means that the C _max and AUC ratios of absorption of active agent from the formulation are both about 0.8-1 when taken with water or with 4%, 20%, or 40% ethanol. Means in the range of .2. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can comprise an opioid, amphetamine, or methylphenidate. In one aspect of the invention, the pharmacologically active agent is present in the formulation as the free base. In another aspect of the invention, the active agent is an opioid free base, specifically the free base form of oxycodone.

  In another particularly preferred embodiment of the invention, an abuse-resistant oral pharmaceutical formulation is provided comprising a controlled release carrier system that can provide a reduced risk of misuse or abuse. However, the carrier system is characterized by a low in vitro solvent extraction rate of the active agent from the formulation. A suitable in vitro test method, technique, and apparatus for determining whether a formulation is properly characterized as having a “low in vitro solvent extraction rate” is described in Example 4 below. In summary, it is possible to place the test formulation in a suitable amount of easily obtainable liquids such as water, alcohol (ethanol), soft drinks, vinegar, sodium bicarbonate solution, and the like. After a suitable time (and with suitable stirring or heating, for example), it is possible to test the liquid “extraction solvent” for the presence of the extracted active agent. For the purposes of such testing, any number of such liquids can be combined into a “group” of extraction solvents. Thus, in these preferred embodiments, the “abuse-resistant” formulation is resistant to extraction over a group of common household solvents. That is, at ambient temperature (RT), all of the following solvents: cola soft drink (pH about 2.5), household vinegar (pH about 2.5), saturated sodium bicarbonate solution (pH about 8.5), and After 60 minutes extraction in ethanol (100 proof), less than 30% of the starting active agent is extracted from the formulation. In certain preferred embodiments, the active agent can be an opioid, a CNS inhibitor, or a CNS stimulant that has a particularly high probability of abuse, diversion, or other misuse. Preferably, the active agent can comprise an opioid, amphetamine, or methylphenidate. In one aspect of the invention, the pharmacologically active agent is present in the formulation as the free base. In another aspect of the invention, the active agent is an opioid free base, specifically the free base form of oxycodone. In a particularly preferred embodiment of the present invention, the carrier system is further characterized by not having any significant effect on the absorption of the pharmacologically active agent from the formulation when the subject simultaneously takes the formulation with ethanol.

  In another particularly preferred embodiment of the invention, a controlled release oral pharmaceutical formulation comprising an opioid active agent is provided. However, the formulation provides effective analgesia to the subject when administered on a twice daily (BID) dosing schedule, and the formulation further includes one or more anti-abuse performance characteristics (the methods of Examples 4 and 8). Can be evaluated using). As used herein, the term “controlled release” refers to controlled release of an active agent (eg, extended release, delayed release, or any optional) so that it is pharmacologically available within the recipient's system. Any physics of the formulation (contains, comprises, or consists of) a pharmaceutical formulation and one or more active agents that provides a release capability that otherwise attenuates or modifies immediate release It is used in its broadest sense to include chemical and / or chemical associations. In addition, the formulations provide subjects with “effective analgesia” when administered on a twice daily (BID) dosing schedule, including acute or chronic pain symptoms when such formulations are administered. Cause reduction (eg, improvement, attenuation, reduction, reduction, blockage, suppression, or prevention) of at least one sign or symptom of a pain symptom. The ability of a formulation to provide effective analgesia can be readily assessed by one skilled in the art using standard clinical trial techniques, including those utilized in Example 7f.

  In certain embodiments, the controlled release formulation provides one or more of the following abuse-resistant performance characteristics. (A) When subjected to extraction in 100 proof ethanol for 5 minutes at room temperature, the formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid. (B) When subjected to extraction into vinegar at room temperature for 5 minutes, the formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid. (C) The formulation releases less than about 5% of the opioid, preferably less than about 2% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at room temperature for 5 minutes. (D) When subjected to extraction into a cola soft drink for 5 minutes at room temperature, the formulation releases less than about 10% of the opioid, preferably less than about 5% of the opioid. (E) When subjected to extraction into 100 proof ethanol over 60 minutes at room temperature, the formulation releases less than about 20% of the opioid, preferably less than about 11% of the opioid. (F) When subjected to extraction into vinegar for 60 minutes at room temperature, the formulation releases less than about 20% of the opioid, preferably less than about 12% of the opioid. (G) When subjected to extraction into a saturated sodium bicarbonate solution at room temperature for 60 minutes, the formulation releases less than about 20% of the opioid, preferably less than about 12% of the opioid. (H) When subjected to extraction into a cola soft drink for 60 minutes at room temperature, the formulation releases less than about 30% of the opioid, preferably less than about 22% of the opioid. (I) When subjected to extraction in 100 proof ethanol for 5 minutes at 60 ° C., the formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid. (J) When subjected to extraction into vinegar at 60 ° C. for 5 minutes, the formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid. (K) The formulation releases less than about 15% of the opioid, preferably less than about 11% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 ° C. for 5 minutes. (L) When subjected to extraction into a cola soft drink for 5 minutes at 60 ° C., the formulation releases less than about 45% of the opioid, preferably less than about 30% of the opioid. (M) When subjected to extraction into 100 proof ethanol for 60 minutes at 60 ° C., the formulation releases less than about 33% of the opioid, preferably less than about 26% of the opioid. (N) When subjected to extraction into vinegar at 60 ° C. for 60 minutes, the formulation releases less than about 33% of the opioid, preferably less than about 20% of the opioid. (O) The formulation releases less than about 33% of the opioid, preferably less than about 23% of the opioid when subjected to extraction into a saturated sodium bicarbonate solution at 60 ° C. for 60 minutes. (P) When subjected to extraction into a cola soft drink at 60 ° C. for 60 minutes, the formulation releases less than about 60% of the opioid, preferably less than about 45% of the opioid. (Q) less than about 20% of the opioid, preferably opioid when subjected to extraction into a group of extraction solvents each containing vinegar, hot tea, saturated sodium bicarbonate, and cola soft drink for 60 minutes each at 25 ° C. Less than about 15%. (R) less than about 15% of the opioid, preferably less than about 12% of the opioid when subjected to extraction into a group of aqueous buffered extraction solutions in the range of pH 1 to pH 12, each at 25 ° C. for 60 minutes. discharge. (S) A group of physically breaking the formulation by crushing, each containing 60 ° C. water at 25 ° C., 60-70 ° C. water, 0.1 N HCL at 25 ° C., and 100 proof ethanol at 25 ° C. for 60 minutes each Releases less than about 40% of the opioid, preferably less than about 35% of the opioid when subjected to extraction into an aqueous extraction solution. And / or (t) physically destroy the formulation by microwave treatment and then into a group of aqueous extraction solutions containing water, 0.1 N HCL, and 100 proof ethanol each for 60 minutes at 25 ° C. When subjected to extraction, it releases less than about 25% of the opioid, preferably less than about 20% of the opioid. All of these anti-abuse performance characteristics can be easily evaluated using standard techniques such as those described in Example 4. Alternatively or additionally, the controlled release formulation described above may provide one or more of the following abuse-resistant performance characteristics. (A) Formulation is controlled release by chewing, buccal oral retention, or simultaneous consumption of alcohol (eg, 4% ethanol (beer), 20% ethanol (enriched wine), or 40% ethanol (distilled liquor)) Less susceptible to dose dumping as a result of physical destruction of sex formulations. (B) The formulation is less susceptible to inhalation abuse techniques (eg, vaporization or smoking, or crushing and nasal inhalation). And / or (c) the formulation is not susceptible to injection abuse techniques (eg, the formulation in the formulation is not syringe inhalable and / or injectable). All of these anti-abuse performance characteristics can be readily evaluated using standard techniques such as those described in Example 8. In certain preferred embodiments, the opioid is oxycodone, oxymorphone, hydrocodone, or hydromorphone and can exist in either a salt form or a free base form. In one particularly preferred embodiment, the opioid is oxycodone.

  The pharmacologically active agent contained in the abuse-resistant oral pharmaceutical preparation according to the present invention has a desired pharmacological and / or pharmacological and / or systemic action when administered to an organism (human or animal subject). Any type of biologically active compound or substance composition that causes a physiological effect may be included. The term thus encompasses and can be used interchangeably with compounds or chemicals traditionally regarded as drugs, biopharmaceuticals (including molecules such as peptides, proteins, nucleic acids), and vaccines. The term further encompasses compounds or chemicals that are traditionally considered diagnostic agents.

  Thus, examples of such biologically active compounds or substance compositions useful for practicing the present invention include opioids, CNS inhibitors, and CNS stimulants, as well as proteins, hormones, chemotherapeutic agents Antiemetics, antibiotics, antiviral agents, and other agents. Biologically active compounds of particular interest here are opioids, such as alfentanil, allylprozin, alphaprozin, anireridine, apomorphine, apocodeine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, Cyclolphene, prenorphine, desomorphin, dextromoramide, dextromethorphan, dezocine, dianpromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthianbutene, dioxafetil butyrate, dipipanone, eptazocine, etoheptazine, ethylmethylthian Butene, ethylmorphine, etonitazen, fentanyl, heroin, hydrocodone, hydroxy Methylmorphinan, hydromorphone, hydroxypetidin, isomethadone, ketobemidone, levalorphan, levorphanol, levofenacil morphane, levomethanphan, lofentanil, meperidine, meptazinol, metazosin, methadone, methylmorphine, methopone, morphine, mirophine, Nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, narolphine, normorphin, norpipanone, omefentanil, opium, oxycodone, oxymorphone, papaveretam, pentazocine, fe-equon xone, phenomorphan, phenazosin, phenoperidine, forcodine, pinomidine, pyrimramide , Profeptadine, Promedol, Profador, Properidine, Propyram Propoxyphene, remifentanil, sufentanil, tramadol, tilidine, naltrexone, naloxone, nalmefene, methylnaltrexone, naloxone methiodide, nalolphine, naloxonadine, nalide (nalide), nalmexone, nalbuphine, nalolphine dinicotinate, naltrindole (NTI) , Nartrindole isothiocyanate (NTII), naltriben (NTB), norbinaltolfimine (nor-BNI), tapentadol, β-funaltrexamine (b-FNA), BNTX, cyprodim, ICI-174,864, LY117413 , MR2266, etorphine, DAMGO, CTOP, diprenorphine, naloxone benzoylhydrazone, bremazosin, ethylketocyclazocine, U 0,488, U69,593, spiradrine, DPDPE, [D-Ala2, Glu4] deltorphin, DSLET, Met-enkephalin, Leu-enkephalin, β-endorphin, dynorphin A, dynorphin B, α-neoendorphin, or Among opioids, there may be mentioned nalmefene, naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine, those having the same pentacyclic nucleus as dezocine, or pharmacologically effective esters or salts thereof. Preferred opioids for use in the practice of the present invention include morphine, hydrocodone, oxycodone, codeine, fentanyl (and its analogs), hydromorphone, meperidine, methadone, oxymorphone, propoxyphene, or tramadol, or mixtures thereof. Can be mentioned. More preferred opioids include oxycodone, oxymorphone, hydrocodone, and hydromorphone. With respect to oxycodone, which is the preferred opioid, it may be beneficial to provide a formulation with reduced levels of peroxide degradation products such as αβ unsaturated ketones (ABUK). In such cases, it is possible to subject the controlled release carrier system to techniques for reducing and / or removing peroxide contaminants according to known methods.

  Other biologically active compounds or substance compositions useful for practicing the present invention include prochlorperazine edicylate, ferrous sulfate, aminocaproic acid, potassium chloride, mecamylamine, procainamide, amphetamine (All forms including dexamphetamine, dextroamphetamine, dS-amphetamine, and levoamphetamine), benzphetamine, isoproterenol, methamphetamine, dexmethamphetamine, phenmetrazine, betanecol, methacholine, pilocarpine, atropine, methoscopolamine, Isopropamide, tridihexetyl, phenformin, methylphenidate (all forms including dexmethylphenidate, d-threomethylphenidate, and dl-threomethylphenidate), oct Prenolol, metroprolol, cimetidine, diphenidol, meclizine, prochlorperazine, phenoxybenzamine, thiethylperazine, anisindione, diphenadione erythrityl, digoxin, isoflurofate, reserpine, acetazolamide, metazolamide, bendroflumethiazide, chlor Propamide, tolazamide, chlormadinone, phenglycol, allopurinol, aspirin aluminum, methotrexate, acetylsulfisoxazole, erythromycin, progestins, estrogenic progresterone, corticosteroids, hydrocortisone, hydroacetate Corticosterone, cortisone acetate, triamcinolone, methyltesterone, 17β-estradiol Ethinylestradiol, ethinylestradiol 3-methyl ether, prednisolone, acetic acid 17-hydroxyprogesterone, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, progesterone, norprogesterone, norethinodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac , Indoprofen, nitroglycerin, propranolol, metroprolol, sodium valproate, valproic acid, taxanes such as paclitaxel, camptothecins such as 9-aminocamptothecin, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine Imipramine, levodopa, chloropromazine, Spellin, methyldopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of α-methyldopa hydrochloride, theophylline, calcium gluconate, ferrous lactate, ketoprofen, ibuprofen, cephalexin, haloperiodol, zomepirac, vincamine, diazepam, phenoxybenzamine, β-blockers, calcium channel blockers such as nifedipine, diltiazene, verapamil, lisinopril, captopril, ramipril, fosimopril, benazepril, rivanzapril, cilazapril, silazaprilate, perindopril, zofenopril, enalapril, quinapril, quinapril, etc. It is done.

  Still other biologically active compounds or substance compositions useful for practicing the present invention include immunosuppressants, antioxidants, anesthetics, chemotherapeutic agents, steroids (including retinoids), hormones, Antibiotics, antiviral agents, antibacterial agents, antiproliferative agents, antihistamines, anticoagulants, antiphotoaging agents, melanocyte stimulating peptides, non-steroidal and steroidal anti-inflammatory compounds, antipsychotics, and more Examples include radiation absorbers such as UV absorbers, chemotherapeutic agents, and antiemetic drugs. Thus, anti-infective agents such as nitrofurazone, sodium propionate, antibiotics such as penicillin, tetracycline, oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin, chloramphenicol, erythromycin, and Azithromycin, sulfonamides such as sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole, and antiviral agents such as idoxuridine, antiallergens such as antazoline, metapyrylene, chlor Pheniramine, pyrilamineprofenpyridamine, hydrocortisone, cortisone, hydrocortisone acetate, Oxamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medorizone, prednisolone, prednisolone 21-sodium succinate, and prednisolone acetate, desensitizers such as ragweed pollen antigen, hay fever pollen antigen, dust antigen, and milk antigen, Vaccines such as smallpox, yellow fever, distemper, pig cholera, chickenpox, antitoxin, scarlet fever, diphtheria toxoid, tetanus toxoid, pigeon fever, whooping cough, influenza, rabies, mumps, measles, gray leukitis, and newcastle Disease vaccines, decongestants such as phenylephrine, naphazoline, and tetrahydrazoline, miotics and anticholinesterase agents such as pilocarpine, esperine salicylate, carbachol, diisopropyl Fluorophosphoric acid, iodinated phospholine, and deme potassium bromide, parasympathetic blockers such as atropine sulfate, cyclopentrate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine, sympathomimetic agents such as epinephrine, sedation And hypnotics such as sodium pentobarbital, phenobarbital, sodium secobarbital, codeine, (α-bromoisovaleryl) urea (), carbomar, psychostimulants such as 3- (2-aminopropyl) indole Acetic acid and 3- (2-aminobutyl) indoleacetic acid, tranquilizers such as reserpine, chlorpromazine, and thiopropazate, androgenic steroids such as methyl-testosterone and fluoximes Terones, estrogens such as estrone, 17-β-estradiol, ethinylestradiol, and diethylstilbestrol, progesterone-like agents such as progesterone, megestrol, melengestrol, chlormadinone, etisterone, norethinodrel, 19-norprogesterone , Norethindrone, medroxyprogesterone, and 17-β-hydroxy-progesterone, humoral agents such as prostaglandins such as PGE1, PGE2, and PGF2, antipyretics such as aspirin, sodium salicylate, and salicyl Amides, antispasmodic agents such as atropine, methanthelin, papaverine, and methoscopolamine bromide, antimalarial agents such as 4-aminoquinolines, 8-aminochelin Norins, chloroquine, and pyrimethamine, antihistamines such as diphenhydramine, dimenhydrinate, tripelenamine, perphenazine, and chlorphenetazine, cardioactive agents such as dibenzhydroflumethiazide, flumethiazide, chlorothiazide, and aminotolate, nutrition Agents such as vitamins, natural and synthetic biologically active peptides and proteins such as growth factors, cell adhesion factors, cytokines, and biological response modifiers are all used in the present invention as active agents. It is suitable for. These and other active agents are readily available to those skilled in the art and are also available from Pharmaceutical Sciences, by Remington, 14th Ed., 1979, published by Mack Publishing Co., Easton, Pa .; Medical Chemistry, 3rd Ed. , Vol. 1 and 2, by Burger, published by Wiley-Interscience, New York and Physician's Desk Reference, 56th Ed., 2002, published by Medical Economics Co., New Jersey Yes.

The active agent can be present in a neutral form, as a free base form, or in a pharmaceutically acceptable salt form in the formulations used to make the formulations according to the invention. As used herein, the term “pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness and properties of a neutral active agent and is not particularly ineligible for pharmaceutical use. Pharmaceutically acceptable salts include salts of acidic or basic groups that are groups that can be present in the active agent. Activators having basic properties can form a wide variety of salts with various inorganic and organic acids. Pharmaceutically acceptable acid addition salts of basic active agents suitable for use in the present invention are non-toxic acid addition salts, i.e. those that form salts containing pharmacologically acceptable anions, e.g. Hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate , Tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate Glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1,1′-methylene-bis- (2-hydroxy-3-naphthoic acid) salt)) It is. Active agents that include an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids listed above. Suitable base salts can be formed from bases that form non-toxic salts, examples include aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, and diethanolamine salts. . See, for example, Berge et al. (1977) J. Pharm. Sci. 66 : 1-19.

  In an abuse-resistant oral pharmaceutical formulation according to the present invention, the pharmacologically active agent will be dissolved (completely or partially) or dispersed in a controlled release carrier system. The expression “dissolving or dispersing” is intended to encompass all means of establishing the presence of an active agent within a subject controlled release carrier system, such as dissolving, dispersing, partially dissolving, and partially dispersing, And / or suspension. In addition, in certain embodiments of the invention in which the active agent is in the form of solid particulates suspended in a controlled release carrier system, the bulk is contained within the micron (μm) region and is substantially uniform. In order to provide a particle population having a uniform particle size, it is possible to pre-treat the active agent microparticles in a micronization process as described in Examples 1 and 2 below.

  A pharmacologically active agent, which can include one or more suitable active agents, is based on the total weight of the formulation, depending on the identity of the active agent, the desired dose required for the formulation, and its intended use, In an amount of about 95 to about 0.1 weight percent (wt%), in an amount of about 40-1 wt%, in an amount of about 35-1.3 wt%, or in an amount of about 30-5 wt%. It will be present in the formulation used for making. In certain preferred embodiments, the active agent is present in the formulation in an amount of about 1 to about 10 wt%, and thus about 0.01 mg to 1000 mg or about 0.1 mg to 500 mg or about 2 mg to 250 mg or about 2 mg. It can be filled into a suitable formulation to provide a single dose in the range of ~ 250 mg or about 2 mg to 150 mg or about 5 mg to 100 mg or about 5 mg to 80 mg. In certain preferred embodiments comprising opioid active agents, exemplary single doses include 1, 2, 3, 5, 10, 15, 20, 30, 40, 60, 80, 100, and 160 mg. However, it is not limited to these. In other preferred embodiments comprising a CNS inhibitor or CNS stimulant, exemplary single doses include 5, 10, 15, 18, 20, 25, 27, 30, 36, 40, 50, 54, Examples include, but are not limited to, 60, 70, 80, and 100 mg. The exact amount of active agent desired can be determined by routine methods well known in the pharmacology art and will depend on the type of agent and the pharmacokinetic and pharmacodynamic behavior of the agent. .

  The controlled release carrier system utilized in the abuse-resistant oral pharmaceutical formulations disclosed and claimed herein is a combination of a high viscosity liquid carrier material ("HVLCM"), a network former and a rheology modifier. It is formed. HVLCM is a non-polymeric water-insoluble liquid material having a viscosity of at least 5,000 cP at 37 ° C. that does not crystallize neat under ambient or physiological conditions. The term “water-insoluble” means a material that is soluble in water within a range of less than 1 weight percent under ambient conditions. The term “non-polymeric” refers to an ester or mixed ester that has essentially no repeat units in the acid portion of the ester, or an acid portion that is repeated a small number of functional units in the acid portion. Means ester or mixed ester (ie oligomer). In general, materials having more than 5 identical and adjacent repeating or monomeric units in the acid portion of the ester are excluded by the term “non-polymeric” as used herein. , Dimer, trimer, tetramer, or pentamer-containing materials are included within the scope of this term. When forming an ester from a further esterifiable hydroxy-containing carboxylic acid moiety such as lactic acid or glycolic acid, the number of repeating units is calculated based on the number of lactide or glycolide moieties, not the number of lactic acid or glycolic acid moieties Wherein the lactide repeat unit contains two lactic acid moieties that are esterified by their respective hydroxy and carboxy moieties, and the glycolide repeat unit is defined by their respective hydroxy and carboxy moieties. Contains two esterified glycolic acid moieties. Esters having from 1 to about 20 etherified polyols in the alcohol moiety or from 1 to about 10 glycerol moieties in the alcohol moiety are non-polymeric (when the term is used herein) Is considered. HVLCM can be based on carbohydrates. It can also include one or more cyclic carbohydrates chemically bonded to one or more carboxylic acids. HVLCM also includes one or more non-polymeric esters or mixed esters of carboxylic acids having a viscosity of at least 5,000 cP at 37 ° C. that do not crystallize neat under ambient or physiological conditions. (If the ester contains an alcohol moiety (eg glycerol)). The ester can contain, for example, from about 2 to about 20 hydroxy acid moieties. Various HVLCMs used in the present controlled release carrier system are described in US Pat. Nos. 5,747,058, 5,968,542, and 6,413,536. Are listed. The present invention may utilize any HVLCM described in these patents, but is not limited to any materials specifically described. HVLCM is typically present in the formulations according to the invention in an amount of 30-60% by weight, for example 35-45% by weight.

  In certain preferred embodiments of the invention, the controlled release carrier system comprises sucrose acetate isobutyrate (“SAIB”) as HVLCM. SAIB is a non-polymeric highly viscous liquid at temperatures ranging from -80 ° C to 100 ° C and is a fully esterified sucrose derivative with a nominal ratio of 6 isobutyrate and 2 acetates. The chemical structure of SAIB is depicted herein as FIG. SAIB materials are available from various suppliers, including Eastman Chemical Company, in this case as mixed esters that do not crystallize but exist as very viscous liquids. It is a hydrophobic non-crystalline low molecular weight molecule that is water insoluble and has a viscosity that varies with temperature. For example, pure SAIB exhibits a viscosity of about 2,000,000 centipoise (cP) at ambient temperature (RT) and about 600 cP at 80 ° C. Since SAIB materials have significantly lower viscosity values than established SAIB solutions in some organic solvents, SAIB organic solvent solutions themselves are used in mixers, liquid pumps, and capsule making machines. It has a unique solution-viscosity relationship in that it can be processed using such a conventional apparatus. SAIB is also described, for example, in US Pat. Nos. 5,747,058, 5,968,542, 6,413,536, and 6,498,153. It has application in drug formulation and delivery as described in the document. In the present invention, SAIB can be used as an HVLCM and can be present in quite different amounts. For example, the HVLCM (one or more) in an amount of at least about 30, 35, 40, 50, 60, or 61-99.9 weight percent (wt%) based on the total weight of the formulation used to make the formulation Of any suitable HVLCM) can be used. Typically, SAIB is present in the formulations according to the invention in an amount of 30-60% by weight, for example 35-45% by weight.

  In certain circumstances, providing a SAIB carrier material having a lower peroxide level in order to avoid degradation of various components of the controlled release carrier system and / or active agent by peroxide. Sometimes useful. See, for example, US Patent Application Publication No. 2007/0027105 entitled “Peroxide Removal from Drug Delivery Vehicles”. Various specific pharmaceutical formulations containing about 40 wt% SAIB used in the preparation of suitable formulations are described in the examples.

  As used herein, “rheology modifier” means a substance having both a hydrophobic and a hydrophilic portion. The rheology modifiers used in the practice of the present invention generally have a logarithm of octanol-water partition coefficient ("LogP") of about -7 to +15, preferably -5 to +10, more preferably -1 to +7. It is. In addition, rheology modifiers typically have a molecular weight of about 1,000 daltons or less. Rheology means the deformation and / or flow properties of the liquid material, and rheology modifiers adjust (reduce) and adjust flow properties of HVLCM and other components used in controlled release carrier systems ( Used to perform augmentation). That is, it is used to plasticize HVLCM and other components. Thus, rheology modifiers are plasticizers, typically plasticizers for HVLCM. Rheology modifiers useful in the present invention include, for example, caprylic / capric triglycerides (Migliol 810), isopropyl myristate (“IPM”), ethyl oleate, triethyl citrate, dimethyl phthalate, labrafil, labrasol, Gelucire, And benzyl benzoate. In certain preferred embodiments of the invention, the rheology modifier is IPM. The IPM material is a pharmaceutically acceptable hydrophobic solvent. The rheology modifier, which can include one or more suitable rheology modifier materials, is about 0.1 to about 20 weight percent (wt%) based on the total weight of the formulation used to make the formulation according to the invention. ), Preferably from about 1 to about 18 wt%, more preferably from about 2 to about 15 wt%.

By “network formation agent” is meant a material or compound that forms a network when introduced into a liquid medium (eg, HVLCM or a controlled release carrier system comprising HVLCM). A network former can be added to the liquid formulation so that it forms a three-dimensional network in the formulation when exposed to an aqueous environment. Without wishing to be bound by any particular theory, it is believed that the network-forming agent allows the formation of a micro-network in the formulation when exposed to an aqueous environment. The micro-network formation, at least in part, appear due to a phase transition of the network former (for example, a change in the glass transition temperature T _g). This results in the formation of a network-former skin layer or surface layer at the interface between the formulation and the aqueous environment of the GI tract, and the formation of a three-dimensional micro-network structure of the network-former that has precipitated in the formulation It is thought to be done. The network forwer is selected to have good solubility in the selected solvent used in the formulation, for example, about 0.1 to 20 wt%. In addition, good network formers typically have a Log P of about -1-7. Suitable network formers include, for example, cellulose acetate butyrate (“CAB”), carbohydrate polymers, organic acids of carbohydrate polymers and other polymers, hydrogels, cellulose acetate phthalates, ethyl cellulose, Pluronic, Eudragit, Carbomer, hydroxylpropyl Methyl cellulose, other cellulose acetates such as cellulose triacetate, PMMA, and any other material that can associate, align, or condense to form a three-dimensional network in an aqueous environment. A particularly preferred network former for use in the practice of the present invention is grade 381-20 BP cellulose acetate butyrate ("CAB 381-20" available from Eastman Chemicals). CAB 381-20 has the following chemical and physical properties: 36% butyryl content, 15.5% acetyl content, 0.8% hydroxy content, 185-196 ° C. A non-biodegradable polymeric material having a melting point, a glass transition temperature of 128 ° C., and a number average molecular weight of 66,000-83,000. Preferably, when CAB material is used in the present formulation, it must be subjected to an ethanol wash step (and subsequent drying step) prior to addition to the formulation to remove potential contaminants therefrom. The network former, which may comprise one or more suitable network former materials, is about 0.1 to about 20 weight percent (wt%), preferably about 1 to about 20 based on the total weight of the formulation. It can be present in the formulation at 18 wt%, more preferably from about 2 to about 10 wt%, even more preferably from about 4 to about 6 wt%.

  In addition to the combination of HVLCM, network former and rheology modifier material described above, the controlled release carrier system utilized in the abuse-resistant oral pharmaceutical formulations disclosed and claimed herein further includes: A number of additional excipient materials may be included, including solvents, viscosity enhancing agents, hydrophilic agents, surfactants, and stabilizers.

  The term “solvent” as used herein means any substance that dissolves other substances (solutes). To dissolve one or more of the following ingredients: HVCLM, activator, network former, rheology modifier, viscosity enhancer, hydrophilic agent, surfactant, and stabilizer, the present invention It is possible to use a solvent in the controlled release carrier system according to the above. Preferably, the solvent can dissolve both the HVLCM and the network former. In addition, materials that can function as rheology modifiers in certain controlled release carrier systems can also serve as solvents for one or more components (eg, HVLCM or active agent) or other carrier systems And can only function as a solvent. An example of such a solvent is IPM, which is a hydrophobic solvent. Thus, in one embodiment of the invention, the formulation can include both hydrophilic and hydrophobic solvents. Suitable organic solvents for use in the present invention include, but are not limited to: Substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone (2-pyrrole), triacetin, esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate, and Dimethyl carbonate, fatty acids such as acetic acid, lactic acid and heptanoic acid, mono, di, and tricarboxylic acid alkyl esters such as 2-ethoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malo , Diethyl gluconate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate (IPM), dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, Ethyl citrate, acetyl tributyl citrate, glyceryl triacetate, alkyl ketones such as acetone and methyl ethyl ketone, ether alcohols such as 2-ethoxyethanol, ethylene glycol dimethyl ether, glycofurol, and glycerol formal, alcohols such as benzyl Alcohol, ethanol, and propanol, polyhydroxy alcohols such as propylene glycol, polyethylene glycol (PEG), glycerin (glycerol), 1,3-butylene glycol, and isopropylidene glycol (2,2-dimethyl-1,3- Dioxolone-4-methanol), solketal, dialkylamides such as dimethylformamide, dimethylacetamide, di Tyl sulfoxide (DMSO) and dimethyl sulfone, tetrahydrofuran, lactones such as ε-caprolactone and butyrolactone, cyclic alkylamides such as caprolactam, aromatic amides such as N, N-dimethyl-m-toluamide and 1- Dodecylazacycloheptan-2-one and the like, and mixtures and combinations thereof. Preferred solvents include triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, and glycofurol. In one particular preferred embodiment, the solvent is triacetin, which is a hydrophilic solvent. The hydrophilic triacetin solvent may preferably provide a hydrophobic / hydrophilic solvent system for the solvent in the controlled release carrier system in combination with the IPM rheology modifier which is a hydrophobic solvent. The solvent, which can include one or more suitable solvent materials, is about 0.1 to about 40 weight percent (wt%), preferably about 1 to about 35 wt%, more preferably based on the total weight of the formulation. Can be present in the formulation from about 10 to about 30 wt%, and even more preferably from about 15 to about 28 wt%.

A “viscosity enhancer” or “second viscosity enhancer” is a material that can be added to a controlled release carrier system to increase the viscosity of the resulting carrier system. Viscosity enhancers can be selected to have good hydrogen bonding capacity, eg, one or more bonding capacity per molecule. In certain cases, viscosity enhancers have very low to insignificant solubility in the formulation. If the agent is soluble, preferably the solubility is less than 50 wt%. Inorganic or mineral viscosity enhancers are preferred if the material has a specific surface area of about 100 m ² / g or more. It is generally known to those skilled in the art using pharmaceutical systems with HVLCM, particularly SAIB, as the viscosity of the controlled release system increases, for example, as the solvent for HVLCM is delivered from the system, or With the addition of the polymeric material, release of the active agent from the carrier system is typically slowed. This is because the HVLCM carrier matrix material is more resistant to the diffusion of the agent from the matrix material. Accordingly, if enhancement of the in vivo pharmacological performance of such a system is desired, for example, if extended / improved release performance is desired to increase the bioavailability of the active agent, the controlled release performance Making an intentional increase (increase) in the overall viscosity of the system may be counterintuitive to those skilled in the art. However, in certain formulations according to the present invention, the addition of a viscosity enhancer provides the enhanced in vivo pharmacological performance required by the present invention as well as enhanced safety properties and / or abuse resistance. It has been found that formulations with can be provided. Suitable viscosity enhancing agents include biodegradable and non-biodegradable polymeric materials. Examples of suitable biodegradable polymers and oligomers include poly (lactide), poly (lactide-co-glycolide), poly (glycolide), poly (caprolactone), polyamide, polyanhydride, polyamino acid, polyorthoester, Polycyanoacrylate, poly (phosphazine), poly (phosphoester), polyesteramide, polydioxanone, polyacetal, polyketal, polycarbonate, polyorthocarbonate, degradable polyurethane, polyhydroxybutyrate, polyhydroxyvalerate, polyalkyleneoxalate, Polyalkylene succinates, poly (malic acid), chitin, chitosan, and even copolymers, terpolymers, oxidized cellulose, hydroxyethyl cellulose, or combinations of these materials or Compounds including but not limited to. Suitable non-biodegradable polymers include polyacrylates, ethylene-vinyl acetate polymers, cellulose and cellulose derivatives, acyl substituted cellulose acetates and derivatives thereof such as cellulose acetate butyrate (CAB) (in the present invention non-erodible network formation Polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, polyvinyl (imidazole), chlorosulfonated polyolefin, polyethylene oxide, and polyethylene. Other suitable materials that enhance viscosity include stiffeners such as clay compounds including talc, bentonite, and kaolin, and silicon dioxide, zinc oxide, magnesium oxide, titanium oxide, and calcium oxide. Metal oxides to be used. In a preferred embodiment of the present invention, colloidal silicon dioxide (Cab-O-Sil) is used as a viscosity enhancer in a controlled release carrier system further containing CAB as a network former. Colloidal silicon dioxide further enhances viscosity at rest (which may be useful for product stability) and functions as a viscosity reducer under conditions of mechanical stress (for controlled release performance) May be useful) and can be characterized as a thixotropic agent. Viscosity enhancer materials, which can include one or more suitable viscosity enhancers, are from about 0.01 to about 10 weight percent (wt%) based on the total weight of the formulation used to make the formulations according to the invention. ), Preferably from about 0.1 to about 6 wt%, more preferably from about 1 to about 2 wt%.

  Materials that can be used as a “hydrophilic agent” in the practice of the present invention include those that have an intrinsic affinity for aqueous systems. For the purposes of the present invention, a material can be considered a hydrophilic agent if it exhibits a water sorption of about 10-100% (w / w). The hydrophilic agent will have a low LogP value. As previously discussed herein, the components used to make the controlled release carrier system according to the present invention include hydrophilic materials (eg, hydrophilic solvents) or materials having at least a hydrophilic portion (eg, There are several types that can be classified as rheology modifiers. Since the HVLCM material used in the present carrier system is hydrophobic, other hydrophilic materials are incorporated into the carrier system to provide a balanced carrier system having both hydrophobic and hydrophilic properties. It can be useful. For example, it is believed that one or more hydrophilic agents can be incorporated into the controlled release carrier system according to the present invention to participate in controlling active agent diffusion from the carrier system. Accordingly, suitable hydrophilic agents include sugars such as sorbitol, lactose, mannitol, fructose, sucrose, and dextrose, salts such as sodium chloride and sodium carbonate, starch, hyaluronic acid, glycine, fibrin, collagen, polymers Examples thereof include, but are not limited to, hydroxylpropylcellulose (“HPC”), carboxymethylcellulose, hydroxyethylcellulose (“HEC”), polyethylene glycol, and polyvinylpyrrolidone. In a particularly preferred embodiment, a controlled release carrier system comprising HEC as the hydrophilic agent is provided. The hydrophilic agent, which can include one or more suitable hydrophilic agent materials, is about 0.1 to about 10 weight percent (wt%) based on the total weight of the formulation used to make the formulation according to the invention. ), Preferably from about 1 to about 8 wt%, more preferably from about 3 to about 6 wt%. As another option, the hydrophilic agent may constitute the “first viscosity enhancer” according to the embodiment of the present invention.

  Materials that can be used as “surfactants” in the practice of the present invention include neutral and / or anionic / cationic excipients. Thus, suitable charged lipids include, but are not limited to, phosphatidylcholine (lecithin) and the like. The surfactant will typically be a nonionic, anionic, cationic or amphoteric surfactant. Examples of suitable surfactants include Tergitol (R) and Triton (R) surfactants (Union Carbide Chemicals and Plastics), polyoxyethylene sorbitans such as TWEEN (R) surfactants (Atlas Chemical) Industries), polysorbates, polyoxyethylene ethers such as Brij, pharmaceutically acceptable fatty acid esters such as lauryl sulfate and salts thereof, amphiphilic surfactants (such as glycerides), Gelucire (saturated polyglycolized glycerides) (E.g., Gattefosse brand), as well as similar materials. Surfactants, which can include one or more suitable surfactant materials, are about 0.01 to about 5 weight percent (wt%) based on the total weight of the formulation used to make the formulations according to the invention. ), Preferably from about 0.1 to about 5 wt%, more preferably from about 0.1 to about 3 wt%.

  Materials that can be used as stabilizers in the practice of the present invention include those that inhibit or reduce the degradation of other substances, i.e., substances in the controlled release carrier system mixed with the stabilizer (e.g., by chemical reaction). Any material or substance that can be mentioned. Exemplary stabilizers are typically antioxidants that prevent oxidative damage and degradation, such as sodium citrate, ascorbyl palmitate, vitamin A, and propyl gallate, and / or reducing agents. . Other examples include ascorbic acid, vitamin E, sodium bisulfite, butylhydroxyl toluene (“BHT”), BHA, acetylcysteine, monothioglycerol, phenyl-α-naphthylamine, lecithin, and EDTA. Such stabilizing materials, which can include one or more suitable materials, are from about 0.001 to about 2 weight percent (wt) based on the total weight of the formulation used to make the formulation according to the invention. %), Preferably from about 0.01 to about 0.1 wt%, more preferably from about 0.01 to about 0.02 wt%.

  Accordingly, an oral pharmaceutical formulation made in accordance with the present invention and comprising a pharmacologically active agent, a controlled release carrier system comprising HVLCM, a network former, a rheology modifier, a hydrophilic agent and a solvent comprises (a) 1.3-35 wt%, such as 5-10 wt%, pharmacologically active agent, (b) 2-10 wt%, such as 4-6 wt%, network-forming agent, (c) 0.1-20 wt%, such as 2-15 wt% (D) 1 to 8 wt%, such as 3 to 6 wt% hydrophilic agent, (e) 10 to 40 wt%, such as 10 to 30 wt% solvent, and (f) 30 to 60 wt%, such as 35 to 45 wt%. Of HVLCM. Typically, HVLCM is sucrose acetate isobutyrate (SAIB), and the network former is selected from cellulose acetate butyrate (CAB), cellulose acetate phthalate, ethyl cellulose, hydroxypropyl methylcellulose, and cellulose triacetate; The rheology modifier is selected from isopropyl myristate (IPM), caprylic / capric triglyceride, ethyl oleate, triethyl citrate, dimethyl phthalate, and benzyl benzoate, and the hydrophilic agent is hydroxyethyl cellulose (HEC), hydroxypropyl Selected from cellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone, and the solvent is triacetin, N-methyl 2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, and glycofurol. Preferably, the HVLCM is SAIB, the network former is CAB, the rheology modifier is IPM, the hydrophilic agent is HEC, and the solvent is triacetin.

  The controlled release carrier system may further comprise a viscosity enhancing agent such as silicon dioxide. Viscosity enhancers are typically present in amounts of 0.1 to 6 wt%, such as 1 to 2 wt%.

  In another optional embodiment, a controlled release carrier system made in accordance with the present invention and comprising a pharmacologically active agent, an HVLCM, a network former, a first viscosity enhancing agent, a hydrophilic solvent, and a hydrophobic solvent; (A) 1.3-35 wt%, for example 5-10 wt% pharmacologically active agent, (b) 2-10 wt%, for example 4-6 wt% network structure-forming agent, (c) 1- 8 wt%, such as 3-6 wt% of the first viscosity enhancer, (d) 10-40 wt%, such as 10-30 wt%, hydrophilic solvent, (e) 0.1-20 wt%, such as 2-15 wt% And (f) 30-60 wt%, such as 35-45 wt% HVLCM. Typically, in this embodiment, the HVLCM is SAIB, the network former is selected from CAB, cellulose acetate phthalate, ethylcellulose, hydroxypropylmethylcellulose, and cellulose triacetate, and the first viscosity enhancer is HEC , Hydroxypropylcellulose, carboxymethylcellulose, polyethylene glycol, and polyvinylpyrrolidone, and the hydrophilic solvent is selected from triacetin, N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, and glycofurol And the hydrophobic solvent is IPM. Preferably, the HVLCM is SAIB, the network former is CAB, the first viscosity enhancing agent is HEC, the hydrophilic solvent is triacetin, and the hydrophobic solvent is IPM.

  The controlled release system can further include a second viscosity enhancer, such as silicone dioxide. The second viscosity enhancing agent is typically present in an amount of 0.1-6 wt%, such as 1-2 wt%.

  After selecting all of the components to make a controlled release carrier system according to the present invention, for example, simply mix HVLCM, rheology modifier, network former, activator, solvent, and any additional additives. By doing so, it is possible to prepare liquid pharmaceutical formulations. The formulation according to the invention is made as a liquid mixture and has several excipient components present in the final formulation in dissolved, suspended or partially dissolved state. A suitable method for compounding or manufacturing the formulation utilizes typical equipment and techniques for pharmaceutical / chemical mixing and handling. Liquid formulations according to the present invention will tend to have exceptionally high final viscosities since they are formed from several highly viscous liquids and solids. Accordingly, the particular equipment and techniques utilized in the manufacture of such formulations are preferably selected to be compatible with such materials. In particular, various excipients, such as network formers, are typically added to the compounded mixture in the solid or semi-solid state, so that they are sieved before being added to the compounding device. It is possible to reduce the size or otherwise. Other solid excipients may require melting before being added to the liquid mixture. HVLCM materials are very high viscosity liquid materials but tend to exhibit dramatic viscosity reductions with increased heating, so the mixing device is heated to accommodate the addition of HVLCM materials or other similar materials. It is possible. However, since the mixing and processing conditions must take into account the final integrity of the formulation, the mixing conditions preferably have a low shear effect on the formulation and / or high heating conditions. Alternatively, it is selected to avoid any extended or overt deviation to low heating conditions. After properly combining the formulations, the appropriate amount of the resulting liquid mixture can be placed in a suitable capsule, such as a gelatin capsule, to provide an oral pharmaceutical formulation. Another alternative liquid formulation may include emulsifying the mixture in water and introducing the emulsion into a capsule.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a rheology modifier, a hydrophilic agent and a solvent, one suitable manufacturing or compounding process comprises the following steps: (i ) Preheating the HVLCM; (ii) mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent; and (iii) dispersing the network former in the solution. Dissolving the network-forming agent in the solution and 5-30% of the rheology modifier, such as 10-20%, or optionally 5-30% of the rheology modifier and 10-20% of the rheology modifier. (Iv) a step of adding and mixing a pharmacologically active agent, a step of adding and mixing a hydrophilic agent, and (v) a step of adding and mixing a viscosity enhancer as the case may be. (Vi) comprises the steps of adding and mixing the rest of the rheology modifier, a. The process may further comprise filling the formulation thus obtained into capsules and optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles.

  Step (i) is performed to reduce the viscosity of the HVLCM, so that it becomes easy to flow and other components can be easily mixed with it. Process (i) can be implemented at 50-65 degreeC or 50-60 degreeC or 55-65 degreeC, for example. Typically, steps (ii) to (vi) are each performed at such temperatures.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a rheology modifier, a hydrophilic agent, and a solvent, a suitable manufacturing or compounding process includes the following steps: (i) HVLCM (Ii) mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent; and (iii) optionally 5 to 5 of the stabilizer and rheology modifier. Mixing a 30% solution, for example 10-20%, with the solution obtained in the previous step, and (iv) a rheology modifier, or the remainder of the rheology modifier if step (iii) Adding and mixing with the solution obtained in step (ii) or (iii), (v) optionally adding and mixing a viscosity enhancer with the formulation obtained in the previous step, and (vi) In the solution obtained in step (iv), or when step (v) is performed, the network structure is dispersed in the solution by dispersing the network structure-forming agent in the solution obtained in step (v). Adding and dissolving the forming agent; (vii) adding and mixing the pharmacologically active agent with the formulation obtained in the previous step; and (viii) adding the hydrophilic agent and the formulation obtained in step (vii). Mixing.

  In addition, the process can further comprise filling the formulation thus obtained into capsules and optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles.

  Again, step (i) is performed to reduce the viscosity of the HVLCM, so that it becomes easy to flow and other components can be easily mixed with it. Process (i) can be implemented at 50-65 degreeC or 50-60 degreeC or 55-65 degreeC, for example. Typically, steps (ii) to (viii) are each performed at such temperatures. However, in this process, a lower temperature can be maintained in steps (ii) to (viii). Therefore, each of these processes can be implemented at 35-65 degreeC like 35-60 degreeC or 40-60 degreeC, for example.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent and a hydrophobic solvent, a suitable manufacturing or compounding process includes the following steps: , (I) preheating the HVLCM, mixing a hydrophilic solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent, and (ii) dispersing the network former in the solution. And (iii) 5-30% of the hydrophobic solvent, for example 10-20%, or optionally 5-30% of the stabilizer and the hydrophobic solvent, for example, A step of mixing 10-20% solution with the formulation, (iv) a step of adding and mixing the pharmacologically active agent, (v) a step of adding and mixing the first viscosity enhancer, and (vi) The second viscosity enhancer A mixing pressure, the steps of adding and mixing the rest of (vii) a hydrophobic solvent can include.

  In addition, the process can further comprise filling the formulation thus obtained into capsules and optionally packaging the filled capsules into single dose blisters or multi-dose plastic bottles.

  Step (i) is performed to reduce the viscosity of the HVLCM, so that it becomes easy to flow and other components can be easily mixed with it. Process (i) can be implemented at 50-65 degreeC or 50-60 degreeC or 55-65 degreeC, for example. Typically, steps (ii) to (viii) are each performed at such temperatures.

  Also, for a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent and a hydrophobic solvent, a suitable manufacturing process or formulation process is (Ii) preheating the HVLCM; (ii) mixing the hydrophilic solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent; and (iii) optionally stable. A step of mixing a solution of 5 to 30%, for example 10 to 20% of the hydrophobizing agent and the hydrophobic solvent with the solution obtained in the previous step, and (iv) the hydrophobic solvent or step (iii) In some cases, the remaining portion of the hydrophobic solvent is added and mixed with the solution obtained in step (ii) or (iii), and (v) optionally, a second viscosity enhancing agent is obtained in the previous step. Adding and mixing with the formulation; vi) In the solution obtained in step (iv), or when step (v) is performed, the network structure-forming agent is dispersed in the solution obtained in step (v) by dispersing the network-forming agent in the solution. A step of adding and dissolving the network-forming agent, (vii) a step of adding and mixing the pharmacologically active agent with the formulation obtained in the previous step, and (viii) a first viscosity enhancing agent obtained in step (vii). Adding and mixing with the blended formulation. The process can further comprise filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle.

  In this process embodiment, step (i) is performed to reduce the viscosity of the HVLCM, so that it becomes easy to flow and other components can be easily mixed with it. . Process (i) can be implemented at 50-65 degreeC or 50-60 degreeC or 55-65 degreeC, for example. Typically, steps (ii) to (viii) are each performed at such temperatures. However, in this process, a lower temperature can be maintained in steps (ii) to (viii). Therefore, each of these processes can be implemented at 35-65 degreeC like 35-60 degreeC or 40-60 degreeC, for example.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a rheology modifier, a hydrophilic agent and a solvent, one suitable manufacturing or compounding process involves the following steps: HVLCM. Pre-heating, mixing the solvent with pre-heated HVLCM to form a homogeneous solution of HVLCM in the solvent, and dispersing the network-forming agent in the solution to dissolve the network-forming agent in the solution Mixing the formulation with 5-30% of the rheology modifier, or optionally a solution of 5-30% of the stabilizer and rheology modifier, and adding and mixing the pharmacologically active agent. And a step of adding and mixing a hydrophilic agent, optionally adding and mixing a viscosity enhancing agent, and adding and mixing the remaining portion of the rheology modifier. Yeah. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a rheology modifier, a hydrophilic agent, and a solvent, a suitable manufacturing process or formulation process includes the following steps: HVLCM first. Preheating to a temperature range of; a step of mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent; and optionally, at a temperature within the second range, the stabilizer and The step of mixing the solution of 5 to 30% of the rheology modifier with the solution obtained in the previous step, and the rheology modifier or the previous step were carried out while maintaining the temperature within the second range. If step, adding the remaining portion of the rheology modifier with the solution obtained in the previous step, and optionally, maintaining the temperature within the second range with the viscosity enhancer Obtained in the previous process The step of adding and mixing with the formulation, and adding and dispersing the network-forming agent in the solution thus obtained while maintaining the temperature of the solution within the second range, the network-forming agent is added to the solution. A step of dissolving, a step of adding and mixing the pharmacologically active agent with the formulation obtained in the previous step while maintaining the temperature within the second range, and a state of maintaining the temperature within the second range, And a step of adding and mixing a hydrophilic agent. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent and a hydrophobic solvent, a suitable manufacturing or compounding process includes the following steps: Pre-heating the HVLCM, mixing the solvent with the pre-heated HVLCM to form a homogeneous solution of HVLCM in the solvent, and dispersing the network-forming agent in the solution A step of dissolving in, a step of mixing 5-30% of the rheology modifier, or optionally a solution of 5-30% of the stabilizer and the rheology modifier with the formulation, and a pharmacologically active agent Adding and mixing, adding and mixing a hydrophilic agent, optionally adding and mixing a viscosity enhancing agent, and optionally adding and mixing the rest of the rheology modifier. . In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle.

  For a formulation formed from a mixture of a pharmacologically active agent, HVLCM, a network former, a first viscosity enhancer, a hydrophilic solvent and a hydrophobic solvent, a suitable manufacturing or compounding process includes the following steps: Preheating the HVLCM to a first temperature range, mixing the solvent with the preheated HVLCM to form a homogeneous solution of HVLCM in the solvent, and optionally at a temperature within the second range. Mixing the solution of 5-30% of the stabilizer and the rheology modifier with the solution obtained in the previous step, and maintaining the temperature within the second range, the rheology modifier, or the previous If the step has been performed (if step), the remaining portion of the rheology modifier is added and mixed with the solution obtained in the previous step, and optionally with the temperature maintained within the second range. , Viscosity enhancer in the previous process A step of adding and mixing with the obtained formulation, and adding and dispersing a network-forming agent in the solution thus obtained while maintaining the temperature of the solution within the second range, thereby forming a network structure in the solution. The step of dissolving the forming agent, the step of adding and mixing the pharmacologically active agent with the formulation obtained in the previous step while maintaining the temperature within the second range, and the temperature within the second range And adding a hydrophilic agent in the state. In addition, the process can include filling the formulation obtained in the process into a capsule and optionally packaging the filled capsule into a single dose blister or a multi-dose plastic bottle.

  Several other suitable laboratory scale, GMP, and commercial processes for making abuse-resistant formulations and formulations according to the present invention are described in Examples 1 and 2 below. Yes.

  In certain preferred embodiments, the oral formulation comprises an active agent and a controlled release carrier system encapsulated in an enclosure or capsule (preferably biodegradable) (eg, a capsule or gelatin capsule (“gel cap”)). It is comprised with the liquid formulation containing this. However, capsules are made of a substance that degrades or otherwise dissociates when exposed to conditions present in the mammalian gastrointestinal tract. Capsules and gel caps are well known in the art of drug delivery, and those skilled in the art can select such capsules appropriately depending on the delivery of a particular active agent. After the capsule is dissolved or separated from the formulation, the formulation according to the present invention generally remains intact, especially in hydrophobic formulations, without emulsification or fragmentation. Pass through.

  In a more particular embodiment, the invention encompasses an oral formulation comprising a liquid formulation contained within a biodegradable capsule. However, the formulation comprises an active agent and HVLCM, and the capsule is made of a substance that degrades when exposed to conditions present in the mammalian gastrointestinal tract. In certain embodiments, the capsule comprises gelatin or a synthetic polymer, such as hydroxylethylcellulose and hydroxylpropylmethylcellulose. The gel cap can be a hard product or a soft product. Examples include polysaccharide-based or hypromellose acetate succinate-based caps (eg, the Vegicap brand available from Catalent). Capsules can also be coated with an enteric coating material such as AQIAT (Shin-Etsu) to delay release. Gelatin capsules are suitable for delivery of liquid formulations such as vitamin E and cod liver oil. Gelatin capsules are storage stable, but when placed in the acidic environment of the stomach (low pH below about pH 4-5), the gelcap dissolves over 1-15 minutes.

  In certain embodiments, the abuse-resistant oral pharmaceutical formulation can be formulated to produce a specific controlled plasma level of the active agent over a specific period of time. This is clearly very important in keeping plasma levels within the appropriate therapeutic window. The appropriate therapeutic window will vary depending on the active agent, but can be in the range from femtogram / mL levels to over microgram / mL levels over a desired period of time. For example, a single dose of the formulation disclosed herein can be used to maintain plasma levels of greater than 5 ng / mL for over 8 hours. In other embodiments, plasma levels achieved using a single dose are greater than 5 ng / mL over 10 hours, greater than 12 hours, greater than 14 hours, greater than 16 hours, greater than 18 hours, or greater than 20 hours. It can be. In yet other embodiments, plasma levels achieved using a single dose are greater than 5 ng / mL, 10 ng / mL over 4, 8, 10, 12, 14, 16, 18, 20, or 24 hours. Can be greater than, greater than 15 ng / mL, greater than 20 ng / mL, greater than 30 ng / mL, greater than 40 ng / mL, or greater than 50 ng / mL. The maximum plasma concentration of the active agent is 0.1 hr to about 24 hr or about 0.25 hr to 10 hr or about 0.25 hr to 8 hr or about 0.5 hr to 6 hr or about 0.5 hr to 4 hr or about 0.5 hr after administration. Reachable at time points of ˜2 hr or about 0.5 hr to 1 hr. The time to maximum plasma concentration can be adjusted by adjusting the various components of the controlled release carrier system as taught herein.

  The plasma level obtained can be adjusted by adjusting the dose of the active agent and / or by adjusting the formulation and other components of the controlled release carrier system, the desired plasma level being any It will depend on the therapeutic window or index for a particular active agent. Determining the desired therapeutic index is within the skill of one of ordinary skill in the art without difficulty.

  The rate of active agent release from the formulation will vary depending on the agent used and the dosage required. Since the release rate can be different in different parts of the GI tract, the release rate can be averaged over the time it passes through the GI tract (about 8-24 hr). Typical average release rates can vary substantially. For many active agents, it is about 0.01-500 mg / hr, 0.5-250 mg / hr, 0.75-100 mg / hr, 1.0-100 mg / hr, 2.0-100 mg / hr, 5 It can be in the range of -100 mg / hr, 10-100 mg / hr, 10-80 mg / hr, 20-50 mg / hr, or about 20-40 mg / hr.

  The dosage regimen for a particular active agent in a subject can be determined by a physician according to standard techniques. It is possible to administer once a day (QD) or twice a day (BID) to maintain sufficient clinical effect, for example, to maintain pain relief.

  It should be noted that the examples described herein are illustrative only and do not limit the scope of the invention in any way.

Example 1: Formulation Preparation (Laboratory Scale Manufacturing Process)
Three different laboratory-scale manufacturing processes for the formulations according to the present invention were developed and implemented as follows. The following ingredients were used to make the formulations used in the process. Oxycodone HCl, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); cellulose acetate butyrate, grade 381-20 BP, ethanol Wash (Eastman Chemicals) (“CAB”); sodium lauryl sulfate NF (“SDS”); and Labrafil M2125 CS (“LAB”). Detailed specifics of five different formulations made using the three laboratory scale manufacturing processes of this Example 1 are disclosed in Table 1 below. The batch size of the various formulations was in the range of 900 g to 1 kg.

The primary mixing equipment used in each lab-scale manufacturing process was Ross Model No. 1 equipped with a propeller-type impeller (4 blades) having a diameter of 2.25 inches. HSM 100 LCI. The mixing vessel used was a 2 liter glass jar with an inner diameter (mixing area) of 4.181 inches. After the addition of SiO _2, a Silverson Mixer (Model No. L4RT) was used in each homogenization process. At this time, homogenization was performed for 10 minutes, and the rotor speed was kept at 6000 rpm. During the homogenization process, the temperature of the bulk material was constantly monitored and kept below 75 ° C. During each other step of the manufacturing process, the bulk temperature was maintained at about 60 ° C. using a water bath throughout, and the mixing speed of the mixing device was held constant at 1500 rpm throughout (but with efficient vortexing). In order to disperse the solid material within the bulk material, the mixing rate was exceptionally increased for a short time when any solid material was added). The mixing time was fixed at 30 minutes after the addition of each material except after the addition of CAB. Each process took about 2 hours to bring the CAB material into solution. At the end of each manufacturing process, the resulting formulation was reheated and injected into the soft gel cap using a standard needle and syringe to provide 10 mg and 40 mg oxycodone gel cap formulations.

All raw materials were used as obtained from the various manufactures with the following exceptions. The active agent (oxycodone HCL) raw material has been found to have a wide variety of particle sizes. Furthermore, it was easy to cause agglomeration under ambient conditions. Therefore, the oxycodone material was subjected to a jet milling process in order to micronize the solid material to a substantially uniform particle size. The jet mill apparatus is model no. 00 Jet-O-Mizer Jetmill (Fluid Energy). The processing conditions used for processing a batch size of about 80 g were as follows. Nitrogen gas (N ₂ ) was used instead of compressed air, the pusher nozzle was set to 100 psi, and the grinding nozzles (nozzles # 1 and # 2) were set to 90 psi. The processing time was about 2 hours. After collection from the jet mill apparatus, micronized oxycodone was passed through a 20 mesh stainless steel screen and weighed. In order to avoid any possible agglomeration of the material being processed, this micronization process was performed immediately before each manufacturing process. The CAB feed was washed with ethanol (EtOH) and then any contaminants that might be present were dried off.

In the first laboratory scale manufacturing process (Process Scheme 1), the order of addition of the various material components was adjusted so that the activator (oxycodone) was added at the end of the process. In previous laboratory scale processes, the CAB / triacetin solution was added to the support material SAIB at the start of the process. In this process scheme 1, the CAB material was dispersed in the SAIB material at the start of the process before the addition of triacetin. A flow diagram for process scheme 1 is shown in FIG. 1A. The process temperature was maintained at 60 ° C. ± 5 ° C. throughout the process experiment. CAB dissolution after the addition of triacetin took about 2 hours. Moreover, it was confirmed by visual observation that it was a transparent viscous liquid not containing any solid aggregates. About 15% of the IPM was added along with BHT and SDS (if used) and the remaining portion was added as a rinse. In addition, a homogenizer was used after adding SiO ₂ into the vortex formed by the impeller.

In the second laboratory scale manufacturing process (Process Scheme 2), the oxycodone activator was added prior to the addition of the HEC material and the SiO ₂ material. A flow diagram for process scheme 2 is shown in FIG. 1B. Again, the process temperature was maintained at 60 ° C. ± 5 ° C. throughout the process experiment. CAB dissolution took about 2 hours. Moreover, it was confirmed by visual observation that it was a transparent viscous liquid not containing any solid aggregates. Then about 15% of the IPM was added along with BHT and SDS (if used) and the remaining portion was added as a rinse. In addition, a homogenizer was used after adding SiO ₂ into the vortex formed by the impeller.

The third laboratory scale manufacturing process (Process Scheme 3) is suitable for scale-up of manufacturing by increasing the viscosity of the formulation (from low viscosity to high viscosity, low shear mixing method) during successive steps of the process. A process was developed to provide a low shear process that seems to be. In addition, oxycodone activator was dispersed in the formulation prior to the addition of CAB material and HEC material. A flow diagram for process scheme 3 is shown in FIG. 1C. The process temperature was maintained at 60 ° C. ± 5 ° C. throughout the process experiment. However, unlike process schemes 1 and 2, all CAB components were added at a much later stage in the process just prior to the final addition of HEC. After the addition of the HEC material, mixing was continued until the CAB material was in solution (providing a clear viscous liquid free of any solid agglomerates as confirmed by visual observation). This took about 2 hours. In addition, a homogenizer was used after adding SiO ₂ into the vortex formed by the impeller.

  To investigate whether the order of addition of raw materials has any effect on the controlled release (dissolution) and abuse resistance (extraction) of the formulation after the manufacture of various formulations using the laboratory scale manufacturing process described above The product performance of the formulations was evaluated. In addition, to evaluate whether there is a significant difference in the resulting viscosity of formulations made using the low shear (Process Scheme 3) method versus the higher shear method, the standard Brookfield viscometer (Digital Rheometer Model Nos. JPII, Model HBDV-III + CP with Programmable / Digital Controller thir 52 p or CV, I L Was used to measure the viscosity of the formulation at a series of temperatures (25, 37, and 60 ° C). As a result of this initial viscosity evaluation, the low-shear (process scheme 3) manufacturing method produces a formulation having a viscosity approximately twice that of the above-described formulation made using the high shear method. found. This double viscosity difference was found over the entire temperature range tested, suggesting that low shear methods can produce formulations with significantly higher final viscosities.

  The controlled release performance of the various formulations prepared in this Example 1 was tested using the in vitro dissolution technique described in Example 3 herein below. The in vitro abuse performance of the various formulations prepared in this Example 1 was tested using the in vitro alcohol extraction technique described in Example 4 herein below. For controlled release performance testing, the formulation containing SDS (Formulation No. 1), when produced using Process Scheme 1, is compared to the same formulation produced using either Process Scheme 2 or 3 Even then, it was found to have a slower cumulative release profile (reduced controlled release performance). From these observations, changes in the order of addition of raw materials can affect the kinetic behavior of release in formulations containing SDS components (in process scheme 1, oxycodone is added in the last step, while In process schemes 2 and 3, it is added much earlier in the process). However, this difference in controlled release performance was not noticeable for formulations that did not contain the SDS component (Formulation Nos. 2-5). The formulation containing LAB (Formulation No. 2) and the remaining formulation without both SDS and LAB (Formulation Nos. 3-5) depend on the manufacturing process used to make the target formulation. And showed no substantial difference in controlled release performance.

  In terms of abuse resistance performance, the formulation containing SDS (Formulation No. 1) was compared with the formulation prepared using Process Scheme 1 when compared to the formulation prepared using Process Scheme 2. The improved abuse-resistant performance suggests the possibility of an addition order effect that may also be consistent with the reduced controlled release performance as described above. Regardless of the manufacturing process, there was no substantial difference observed in the abuse resistance performance of other formulations (Formulation Nos. 2-5).

Example 1a:
A GMP production process for the preparation according to the present invention was developed and implemented as follows. The following ingredients were used to make the formulation. D-Amphetamine sulfate (Cambrex) (“AMP”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP , Ethanol wash ("CAB"); caprylocaproyl polyoxyglyceride ("Gattefose") ("CPG"); Gelucire 50/13 (Gattefosse) ("GEL"); and polyethylene glycol 8000 (Dow Chemical) ("PEG 8000"). Detailed specifics of three different formulations made using this Example 1a GMP manufacturing process are disclosed in Table 2a below. The batch size was up to 500g.

  Temperature control was performed using a VWR immersion circulator and a VWR gravity convection oven model 1320. A micromixer homogenizing assembly for the Ross mixer was used for the final homogenization step. After the final mixing step, the bulk formulation was allowed to cool to room temperature for at least 16 hours (overnight) before filling into capsules. A flow diagram for this GMP manufacturing process (process scheme 6) is shown in FIG. 1D. The specific process conditions used for Formulations 1-3 are as follows:

In Formula 1, the final homogenization was performed at 4000 rpm for 5 minutes. The final product temperature was 51.3 ° C.

In Formula 2, homogenization was performed at 4000 rpm for 10 minutes. The initial product temperature was 69.1 ° C. and the final product temperature was 63.6 ° C.

In Formula 3, the final homogenization was performed at 4000 rpm for 10 minutes. The initial product temperature was 71.5 ° C and the final product temperature was 63.1 ° C.

Example 1b:
A GMP production process for the preparation according to the present invention was developed and implemented as follows. A flow diagram for this GMP manufacturing process (process scheme 7) is shown in FIG. 1E. The process temperature was maintained at 55-70 ° C throughout the process experiment. Mixing of the IPM / BHT mixture into the blended mixture was performed for 15 minutes at 1,500 rpm using a 4 inch impeller. The SiO ₂ introduction step was performed for an additional 2 minutes using a rotor stator at 3,000 rpm. After the addition of SiO _2, the homogenization process was performed for 40 minutes using a 2.5 inch rotor and a slotted stator. The abuse-resistant oxycodone oral formulation used in this Example 1b was prepared using the following ingredients. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); sodium lauryl sulfate (" SLS "); Labrafil M2125 CS (“LAB”); Gelucire 44/14 (Gattefose) (“GEL”); and cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Che) icals) ( "CAB"). The formulation was then filled into size # 00 hard gelatin cap shell to make an 80 mg formulation, which was used as a test capsule. The details of this Example 1b formulation and formulation containing formulation are disclosed in Table 2b below.

Example 1c:
A GMP production process for the preparation according to the present invention was developed and implemented as follows. The following ingredients were used to make the formulation. Hydromorphone HCl (“HMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate Grade 381-20 BP, Eastman Chemicals ("CAB"). The formulation was filled into either size # 1 (HMH1) or # 2 (HMH2-4) gelcap shells. Detailed specifics of three different formulations made using this Example 1c GMP manufacturing process are disclosed in Table 2c below. The batch size was up to 500g.

  A flow diagram for this GMP manufacturing process (process scheme 8) is shown in FIG. 1F. The process was performed as follows. Prior to compounding, the Hydromorphone Active Pharmaceutical Ingredient (API) was milled using a Fluid Energy Jet-O-Mizer jet mill to reduce API particle size. 2 Formulations were made using a Ross HSM-100 LCI overhead mixer equipped with a 1/4 inch 4 blade 45 ° mixing blade. The compounding jar was held in a water bath maintained at 55-65 ° C. throughout the compounding cycle.

Preheated SAIB was added to the compounding jar followed by the triacetin solvent. The contents of the jar were mixed at about 500 rpm for at least 30 minutes. A pre-screened netowrk former (CAB) was gradually added to the blending jar and mixed at 1500-1800 rpm until no CAB granules were observed. Preservative (BHT) dissolved in a portion of rheology modifier (IPM) was added to the compounding jar. The remaining IPM was used to rinse the IPM / BHT container and the rinse was added to the compounding jar. The contents of the jar were mixed for at least 30 minutes at about 1500 rpm. The milled hydromorphone API was then added to the compounding jar and mixed at 2500-3500 rpm for at least 10 minutes. Next, the blended mass was homogenized at 5000 to 9000 rpm for 10 minutes using a Silverson L4RT homogenizer equipped with a rectangular hole rotor stator. During the homogenization step, the temperature of the blended mass was kept below 75 ° C. Next, a hydrophilic agent (HEC) was added to the compounding jar and mixed at 2500-3000 rpm for at least 30 minutes. Next, a viscosity enhancer (SiO ₂ ) was added and the mass was allowed to mix at about 1500 rpm for at least 30 minutes. The blended mass was then homogenized again at about 6000 rpm for 10 minutes using a Silverson L4RT homogenizer equipped with a rectangular hole rotor stator. During this second homogenization step, the temperature of the blended mass was kept below 75 ° C. The blended mass was reheated in an oven before the filling operation.

  The blended mass was filled into hard gelatin capsules and sealed using Capsugel CFS-1000 and 50% ethanol solution for sealing. The capsules were packaged in a plastic bottle with a child safety cap with an induction shield liner.

Example 1d:
A GMP production process for the preparation according to the present invention was developed and implemented as follows. The following ingredients were used to make the formulation. Hydrocodone bitartrate (“HCB”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Gelucire 44/14 (Gattefose) (“GEL”); Cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). The formulation was filled into a size # 3 gelcap shell. Detailed specifics of two different formulations made using this Example 1d GMP manufacturing process are disclosed in Table 2d below. The batch size was up to 500g.

A flow diagram for this GMP manufacturing process (process scheme 9) is shown in FIG. 1G. The process was performed as follows. Formulation was performed using a Ross PDM-2 mixer equipped with a planetary paddle, side scraper and high speed disperser blade. SAIB and surfactant (Gelucire 44/14 (GEL)) were preheated in an oven at 70 ° C. Triacetin solvent (TA) was added to the jacketed mixing bowl and heated to a target processing temperature of 65 ° C. The molten GEL was removed from the oven and dispensed into the mixing bowl. The contents were mixed for 5 minutes using a planetary paddle speed of 20-30 rpm. Heated SAIB was added to the mixing bowl, followed by stabilizer (BHT) dissolved in a portion of the IPM rheology modifier. The remaining IPM was used to rinse the IPM / BHT container, and the rinse was added to the mixing bowl. The bowl contents were mixed for at least 10 minutes at a planetary paddle speed of 20-30 rpm and a disperser speed set at 650-850 rpm until the mixture was visually uniform. Hydrocodone bitartrate API was added to the mixing bowl and mixed for at least 10 minutes using a planetary paddle speed of 20-30 rpm and a disperser speed of 750-950 rpm. Viscosity enhancer (SiO ₂ ) was added and mixed for an additional 10 minutes using the same mixing conditions.

  The contents of the mixing bowl were homogenized at 6000 rpm for 13-17 minutes using a Silverson L4RT homogenizer equipped with a rectangular hole rotor stator. After homogenization, the contents of the mixing bowl were mixed for 30 minutes under vacuum (15-29 inches of mercury) using a planetary paddle speed of 20-30 rpm to degas the mass. After releasing the vacuum, a mesh forming agent (CAB) that had been sieved in advance was added to the mixing bowl, followed by the hydrophilic agent (HEC) that had been sieved in advance. The blended mass was mixed under vacuum (15-29 inches of mercury) using a planetary paddle speed of 25-45 rpm and a disperser speed of 200 rpm. During this final mixing step, the blended mass was mixed for at least 60 minutes until no CAB granules were observed.

  The blended mass was reheated in an oven before the filling operation. The blended mass was filled into hard gelatin capsules and sealed using Capsugel CFS-1000 and 50% ethanol solution for sealing. Capsules were packaged in plastic bottles with child safety caps.

Example 2: Formulation Preparation (Commercial Scale Manufacturing Process)
Two different commercial scale manufacturing processes for the formulations according to the present invention were developed and implemented as follows. The following ingredients were used to make the formulation. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Detailed specifics of the formulation made using the commercial scale manufacturing process of this Example 2 are disclosed in Table 3 below.

  All raw materials were used as obtained from various manufactures with the following exceptions. Oxycodone base materials have been found to have a wide variety of particle sizes that can affect the uniformity of the final product. Therefore, the oxycodone material was subjected to a jet milling process in order to micronize the solid material to a substantially uniform particle size. The specific micronization process used is described in detail below. In addition, the CAB feed was washed with ethanol (EtOH) and then dried to remove any contaminants that might be present.

Two different commercial scale manufacturing processes have been developed for the formulations according to the invention. A schematic diagram of each process (hereinafter Process Scheme 4 and Process Scheme 5 respectively) is provided in FIG. In the first commercial process (Process Scheme 4), compounding was performed on a 45 kg scale. In the second process (process scheme 5), blending was performed on a 150 kg scale. The same material was used in both processes, but there were some differences in the method. One difference was the order of addition of ingredients during manufacture to enhance mixing and efficiency during the compounding process. For example, in process scheme 5, the IPM component and the SiO ₂ component are added earlier in the process and the CAB component is added later in the process to reduce the liquid viscosity during the first part of the compounding process. did. Another difference in the oral formulation made by the process was that capsules filled according to process scheme 4 did not seal, but capsules filled according to process scheme 5 were liquid encapsulated microspray from Capsugel. It was sealed using a seal processing (LEMS) process. A comparison of manufacturing processes and equipment is shown in Table 4.

Formulation for Process Scheme 4 was performed using a Ross VMC-10 mixer equipped with SLIM. Thus, all references to a specific rpm number throughout this blending process correspond to this model. In the first step, sucrose acetate isobutyrate (SAIB) was preheated to 50-65 ° C. and then added into the compounding tank at an anchor speed of 20-40 rpm. The temperature of SAIB was maintained at 50-60 ° C. In the second step, triacetin (TA) was added into the compounding tank and mixed at an anchor speed of 20-40 rpm and a disperser speed of 700-2000 rpm. The contents of the tank were mixed to obtain a uniform solution of SAIB in triacetin. Again, the mixture temperature was maintained at 50-60 ° C. In the third step, cellulose acetate butyrate (CAB) that had been previously sieved was introduced into the tank using high shear dispersion during addition to prevent the formation of agglomerates. Mix tank contents using 20-50 rpm anchor speed, 700-4500 rpm rotor stator speed, and 700-3500 rpm disperser speed until the CAB is completely dissolved to form a clear liquid formulation. did. After formation, the contents of the vessel were mixed for an additional 30 minutes using the same anchor speed, rotor stator speed, and disperser speed. In the fourth step, a solution containing about 15% portion of butylated hydroxytoluene (BHT) and isopropyl myristate (IPM) was prepared in a separate container. A 10% portion of the IPM may be set aside for use as a rinsing solvent in later stages of the process. The remaining amount of IPM-BHT solution was added to the compounding vessel and subsequently mixed using an anchor speed of 20-50 rpm and a disperser speed of 700-3500 rpm to achieve uniformity. After the formation of a uniform blend mixture, the vessel contents were mixed for an additional 5 minutes using the same anchor and disperser speeds. During additional mixing, the stator was jogged at 700-1200 rpm as needed. Again, the blended mixture temperature was maintained at 50-60 ° C. In the fifth step, oxycodone (base) is introduced into the compounding tank and mixed using an anchor speed of 20-50 rpm, a disperser speed of 700-3500 rpm, and a rotor stator speed of 800-4500 rpm to achieve uniformity. did. The blending mixture temperature was maintained at 55-65 ° C. The vessel contents were mixed for at least another 2 minutes using the same anchor speed, disperser speed, and rotor stator speed. In the sixth step, hydroxyethyl cellulose (HEC) is introduced into the vessel using high shear dispersion upon addition, using an anchor speed of 20-50 rpm, a disperser speed of 700-3500 rpm, and a rotor stator speed of 800-4500 rpm. To achieve uniform dispersion. The tank contents were mixed for an additional 2 minutes using the same anchor speed, disperser speed, and rotor stator speed. Again, the blend mixture temperature was maintained at 55-65 ° C. In the seventh step, using a high shear dispersion introduced colloidal silicon dioxide (SiO ₂₎ in a bath during the addition, the anchor speed of 20～50Rpm, disperser speed of 700～3500Rpm, and rotor stator speed of 800~4500rpm And mixed. The vessel contents were mixed for at least another 2 minutes using the same anchor speed, disperser speed, and rotor stator speed. Again, the blend mixture temperature was maintained at 55-65 ° C. In the eighth step, IPM was introduced into the vessel and mixed using an anchor speed of 20-50 rpm, a disperser speed of 700-2000 rpm, and a rotor stator speed of 1500-3000 rpm. The contents of the tank were continuously mixed using an anchor and kept at 50-60 ° C. The final blended mass was degassed by vacuum and flushed with 4-5 psig nitrogen for at least 5 minutes. A controlled release formulation mass is filled into hard gelatin capsules to make an abuse-resistant oral formulation according to the present invention and then a single dose blister or multi-dose plastic bottle with a pediatric safety closure for clinical delivery Packaged in.

Formulation for Process Scheme 5 was performed using a Ross PVM-40 mixer equipped with SLIM. Thus, all references to specific rpm numbers throughout the formulation procedure described below correspond to this model. In the first step, sucrose acetate isobutyrate (SAIB) was preheated to 50-65 ° C. and added to the compounding tank. In the second step, triacetin was added to the compounding tank. In the third step, the butylated hydroxytoluene / isopropyl myristate solution is dispensed by dispensing a portion of isopropyl myristate (IPM) (the rest of the IPM is added in the next step) into individual stainless steel containers. Prepared. Butylated hydroxytoluene (BHT) was added to the vessel and the solution was mixed for at least 10 minutes until the BHT was dissolved. Next, the BHT / IPM solution was added to the compounding tank. In the fourth step, IPM was added to the blending tank and mixed until uniform using an anchor speed of 10-50 rpm and a disperser speed of 1-2550 rpm. The mixture temperature was maintained at 35-50 ° C. In the fifth step, colloidal silicon dioxide (SiO ₂ ) is introduced into the compounding tank, the anchor speed is 10 to 50 rpm (eg 20 rpm), the disperser speed is 1 to 2550 rpm (eg 1000 rpm), and 1 to 3600 rpm (eg 2500 rpm). ) To achieve uniform dispersion. Again, the mixture temperature was maintained at 35-50 ° C. The tank contents were mixed for an additional 2-4 minutes using the same anchor speed, disperser speed, and rotor stator speed. In the sixth step, cellulose acetate butyrate (CAB) is introduced into the compounding tank, the anchor speed of 10 to 50 rpm (eg 20 rpm), the disperser speed of 1 to 2550 rpm (eg 1500 rpm), and 1 to 3600 rpm (eg 3000 rpm). ) Rotor stator speed. The blending mixture temperature was kept at 40-60 ° C. The tank contents were mixed for an additional 2-4 minutes using the same anchor speed, disperser speed, and rotor stator speed. In the seventh step, oxycodone (base) is introduced into the compounding tank, the anchor speed of 10 to 50 rpm (eg 20 rpm), the disperser speed of 1 to 2550 rpm (eg 1500 rpm), and the speed of 1 to 3600 rpm (eg 3000 rpm). Was used to achieve uniform dispersion. Again, the controlled release formulation mixture temperature was maintained at 40-60 ° C. The tank contents were mixed for an additional 2-4 minutes using the same anchor speed, disperser speed, and rotor stator speed. In the eighth step, hydroxyethyl cellulose (HEC) is introduced into the compounding tank, the anchor speed is 10 to 50 rpm (eg 20 rpm), the disperser speed is 1 to 2550 rpm (eg 1500 rpm), and 1 to 3600 rpm (eg 3000 rpm). Mixing using rotor stator speed. Again, the controlled release formulation mixture temperature was maintained at 40-60 ° C. The tank contents were mixed for an additional 2-4 minutes using the same anchor speed, disperser speed, and rotor stator speed. The final formulated controlled release formulation mass at 14 mm Hg was degassed by vacuum for at least 2 hours using an anchor speed of 10-50 rpm (eg 20 rpm) and a dispersion speed of 1-2250 rpm (eg 1250 rpm). The compounded controlled-release compound mass was filled into hard gelatin capsules to prepare an abuse-resistant oral preparation according to the present invention. More specifically, the formulated controlled release formulation mass was encapsulated using a Zanasi Liqui-Fill encapsulation machine and sealed using a LEMS 30 capsule sealer. Initially, the blended mass was transferred from the Ross PVM-40 mixer to the Zanasi hopper. The transfer line was heated to a temperature of 55-65 ° C. using a heated hose controller. Next, a Zansai Liqui-Fill encapsulation machine was prepared by adjusting the stroke scale until the proper filling weight was obtained, and the temperature of the filling mass was maintained at 60-65 ° C. Depending on the size of the formulation capsule, different filling nozzles were designed with different nozzle diameters (eg 1.2-2.0 mm) for use in the encapsulator. For 5 mg, 10 mg, and 20 mg capsule formulations, a 1.2 mm diameter nozzle is used. For 30 mg or 40 mg capsule formulations, a 1.5 mm diameter nozzle is used. The filled capsule formulation is then removed from the Zansai Liqui-Fill encapsulation machine into a collection container, sealed using Capsugel's LEMS 30 capsule sealer (liquid encapsulated microspray seal process), and the child safety closure is Packaged in single-dose blister or multi-dose plastic bottles provided.

  In some cases, the oxycodone base used in Process Scheme 4 or Process Scheme 5 was micronized. Micronization of oxycodone was performed using a Hosokawa Alpine spiral jet mill. Supply comprising non-micronized opioids in the presence of injection and grinding air pressures adapted to provide the desired rheological behavior in the chamber required to effect mutual collision of opioid particles during operation The material is poured into a flat cylindrical grinding chamber, which has nozzles arranged tangentially on the peripheral wall. Appropriate velocities and pressures of jetting air pressure (eg, 6.8 Bar injector air pressure) and grinding air pressure (eg, 6.2 Bar) are applied to cause particle-to-particle collisions and interaction with the chamber walls. In order to obtain a constant flow of oxycodone into the spiral jet mill, the injector gas pressure was always about 0.3-0.7 Bar higher than the grinding pressure. Producing micronized particles in this way provides an opioid preparation having a reduced particle size (particle size is less than about 10 μm). Larger particles are retained in the mill by centrifugal (mass) force, while fine micronized particles are collected away from the mill by air stream (drag). A set of process parameters that can be used in the method for preparing a micronized opioid preparation in a jet gas mill include 4 kg batch size, +3 mm injector clearance default, 40-50 g / min feed rate, 6. A grinding gas pressure of 8 bar and an injector gas pressure of 6.2 bar are mentioned. Immediately after micronization, in order to preserve the integrity of the micronized particles, the micronized oxycodone is packaged in a plastic bag with a desiccant and then stored in a plastic drum. This is necessary to retain the stabilized micronized opioid particle preparation. Micronized opioids, particularly salt forms such as oxycodone HCl and hydromorphone HCl, are hygroscopic. To prevent agglomeration and / or fused particles, it is necessary to dry and package immediately. For example, micronized oxycodone is placed in a labeled antistatic bag and secured by fastening the open end of the bag with a cable or twist tie. The antistatic bag is placed in the polybag with the antistatic bag separated from the polybag with a layer of 8 units, silica gel, printer, Natrasorb (registered trademark) S Tyvek (registered trademark) four-sided seal bag desiccant. The The label on the antistatic bag is inspected to ensure that it is visible through the polybag, and the polybag is sealed at its open end. The polybag is placed in an HDPE (high density polyethylene) drum with the polybag separated from the drum with a layer of eight units, silica gel, printer, Natrasorb® S Tyvek® four-way seal bag desiccant. Be placed. The lid is placed on the open end of the drum and is secured by a side lever lock (SSL) using a uniquely numbered security locking tag. Such desiccant packaged and stored micronized opioid preparations can be used in manufacturing processes, including the compounding processes described herein.

Example 3: Analysis of the formulation (in vitro dissolution test procedure)
In order to evaluate the controlled release performance of the formulations according to the present invention, two in vitro dissolution test methods were developed as follows. The first dissolution method (Method 1) is based on USP <711> Method A for delayed release formulations, and consists of a two-step medium (initial volume 750 mL 0.1 N HCl acid as dissolution medium, followed by Use USP dissolver type 2 (without basket) with pH 6.8 by addition of 250 mL sodium phosphate buffer after 2 hours. A two-stage medium was selected to simulate the pH range during which the formulation releases the active agent while passing through the GI tract. A stainless steel coiled wire type 316 is used as a sinker to ensure that the formulation remains at the bottom of the dissolution vessel during the release rate test.

  The second dissolution method (Method 2) was optimized to evaluate the controlled release performance of the controlled release formulation according to the present invention with 5, 10, 20, 30 and 40 mg of active agent. In this regard, the unique controlled release characteristics of the dosage formulation according to the present invention are the rate or extent of active agent release as standard dissolution methods and devices are observed in in vivo pharmacokinetic studies. There is no possibility of having a close relationship. This is mainly due to the use of very hydrophobic excipients (eg SAIB and IPM) in the dosage formulation according to the present invention resulting in a composition that produces a controlled release mass with low water permeability. Thus, this second method provides a better reflection of in vivo release with the enhancement of the previous method (Method 1). The new method is a USP melter equipped with a stainless steel fixed basket assembly (type 316, 20 mesh basket with modification of 20 mesh screen sealing) coupled to a modified conical low-loss evaporation cover on the dissolver. Use a type 2 paddle configuration. These modifications were made to traditional equipment to place the formulation in the high shear flow zone of the USP dissolver using increased paddle speed to increase media flow in the dissolver. This new fixed high flow zone is located just above the rotating paddle. During the test, perfusing the dissolution medium through the fixed basket facilitates the release of the active agent from the entire surface area of the formulation and thereby any surface that may result from placing the formulation at the bottom of the dissolution vessel The boundary layer limit is also overcome. A pictorial diagram of a modified dissolution tank and paddle with a fixed basket assembly is provided as FIG. In addition to the fixed basket assembly, a screen sealing in the mesh basket was developed to prevent the formulation from floating in the basket.

  In addition to the fixed basket assembly, a screen sealing in the mesh basket was developed to prevent the formulation from floating in the basket. Suitable fixed basket assemblies are available and can be purchased as a kit from Varian. The kit contains a mesh basket (10, 20, or 40 mesh) that is attached to the basket shaft. A hole in the evaporative cover of the lysing tank allows the basket shaft to be secured thereto. However, the evaporation cover provided in the kit is not ideal for use in long-term controlled release tests. Because the cover is flat and contains large cutouts, it can be easily removed from the melting apparatus. Throughout the 24-hour dissolution test time, use of the cover provided with the kit will result in significant media loss due to evaporation. Evaporative media loss will ultimately result in a release rate profile that is greater than expected. A conventional dissolution test using the formulation according to the present invention actually gave a controlled release rate profile exceeding 100% release. Therefore, an alternative to the kit evaporation cover was developed.

  The dissolution profiles using 20 mesh basket / 20 mesh screen sealing and 40 mesh basket / no sealing were confirmed to be identical. A 20 mesh basket was chosen to maximize the hydrodynamic flow of the dissolution medium through the basket while minimizing formulation leakage from the basket. Screen sealing is used to confine the formulation in the basket and improve assay variability.

  In addition, Method 2 uses a single phase dissolution medium (0.1N HCl with 0.5% (w / v) sodium dodecyl sulfate (SDS)). The addition of surfactant (SDS) to the dissolution medium increases the ability of the medium to wet the hydrophobic controlled release mass during testing.

Finally, a reverse phase HPLC method was used to determine the active agent concentration of the formulation sample obtained from this dissolution test method of Example 3. The mobile phase of the first dissolution method (Method 1) is prepared in two steps, while the mobile phase of the second dissolution method (Method 2) is prepared in one step. A summary of the method parameters for Methods 1 and 2 is provided below as Table 5.

Example 3a: The following in vitro dissolution test was performed to characterize the in vitro release of an abuse-resistant oxycodone oral formulation over a range of contents (10 mg, 20 mg, and 40 mg content).

The abuse-resistant oxycodone oral formulation used in Example 3a was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Formulations are made using commercial scale manufacturing methods (process scheme 4 or 5 as described above) and then filled into size # 00, # 1, or # 2 gel cap shells 10, 20, And 40 mg formulations were made and used as test capsules. The details of this Example 3a formulation and formulation containing formulation are disclosed in Tables 6 and 7 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 2 described above. The only difference is that the sample time points were at 0.5 hours, 1, 2, 3, 6, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. Two sets of eight 40 mg formulations (n = 16), one set of eight 20 mg formulations (n = 8), and one set of eight 10 mg formulations (n = 8). Two sets of 40 mg formulations were tested using two different dissolver systems. The average data from the four sets of test capsules is summarized in Table 8 below. The release profile from the test capsule is shown in FIG. As can be seen from these data, the two sets of 40 mg formulations had comparable release profiles. In addition, the 10 mg and 20 mg formulations exhibited a faster release rate when compared to the 40 mg formulation. Since the fraction of active agent at or near the formulation surface increases with increasing surface area to volume ratio, these results are generally faster for smaller capsules (formulations having a larger surface area to volume ratio). Consistent with the concept of providing a positive release.

Example 3b: (a) To characterize the in vitro release of an abuse-resistant oxycodone oral formulation over a series of contents (5 mg, 20 mg, and 40 mg content) by a multi-media dissolution test, (b) produced at two different production sites To demonstrate dissolution profile similarity between different drug product lots, and (c) between two different drug product lots (5 mg and 40 mg content) manufactured with different purity grade active agents (oxycodone) The following in vitro dissolution test was performed to demonstrate dissolution profile similarity.

The abuse-resistant oxycodone oral formulation used in this Example 1b was prepared using the following ingredients. Oxycodone base, micronized (“OXY”), grade 2 (specified to contain 0.25% (w / w) or less of 14-hydroxycodeinone (14-HC)) or grade 1 (0. Both grades are obtained from Norramco, Inc (Athens Georgia); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil) ®, Cabot Corp (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”) "); Triacetin USP (" T "); And cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Chemicals) (" CAB "). Formulations are made using commercial scale manufacturing methods (process scheme 4 or 5 as described above) and then filled into size # 00, # 1, or # 4 hard gelatin cap shells, 5, 20 And 40 mg formulations were made and used as test capsules.

The details of this Example 3b formulation and formulation containing formulation are disclosed in Tables 9 and 10 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 2 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 2, 3, 6, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. (Test 1, manufacturing location 1) 12 40 mg formulations (n = 12), 12 20 mg formulations (n = 8), and 12 5 mg formulations (n = 12), (Test 2, manufacturing location 2) 12 40 mg formulations (n = 12), 12 20 mg formulations (n = 8), and 12 5 mg formulations (n = 12), and (Test 3, high purity OXY) 12 40 mg formulations (n = 12), and 12 5 mg formulations (n = 12). The average data obtained from tests 1-3 are summarized in the following tables 11-13. The release profiles obtained from tests 1 to 3 are summarized in FIGS. 5, 6 and 7 together with a common content and dissolution medium.

  As can be seen from these results, test capsules made with three different active agent contents (5 mg, 20 mg, and 40 mg) and produced at two different scales and at two different locations were prepared with three different aqueous buffers. Equivalent dissolution performance is shown in the system (pH 1, 4.5, and 6.8). In addition, test capsules made with two different active agent contents (5 mg and 40 mg) and two different active agent grades show equivalent dissolution performance in the same buffer system. Furthermore, the test capsule content and the cumulative release rate for the dissolution medium are generally the fastest with 0.1 N HCl, slightly slower with acetate buffer and the slowest with phosphate buffer. This release performance was attributed to the relatively low solubility of the active agent (oxycodone base) at pH 6.8 (the pKa of oxycodone base is 8.65).

Example 3c:
In order to characterize the in vitro release of an abuse-resistant oxycodone oral formulation across a series of formulations, the following in vitro dissolution test was performed. The abuse-resistant oxycodone oral formulation used in Example 3c was prepared using the following ingredients. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); sodium lauryl sulfate (" SLS "); Labrafil M2125 CS ("LAB"); Gelucire 44/14 (Gattefose) ("GEL"); and cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Che icals) ( "CAB"). Formulations are made using commercial scale manufacturing methods (Process Scheme 4 or 5 described above) and then filled into size # 00 hard gelatin cap shell to make an 80 mg formulation, which is the test capsule. Used as. The details of this Example 3c formulation and formulation containing formulation are disclosed in Table 14 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 2 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 1, 2, 3, 6, 10, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. Each of 6 (n = 6) formulations OXY1-OXY 9. Average dissolution data from 9 sets of test capsules are summarized in Table 15 below.

Example 3d:
In order to characterize the in vitro release of abuse-resistant hydromorphone oral formulations over a series of contents (8 mg and 16 mg contents) and over a series of formulations, the following in vitro dissolution test was performed.

The abuse-resistant hydromorphone oral formulation used in Example 3d was prepared using the following ingredients: Hydromorphone HCl (“HMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate Grade 381-20 BP, Eastman Chemicals ("CAB"). A formulation was made using the GMP manufacturing method of Example 1d above (process scheme 8), then filled into a gel cap shell of size # 1 (HMH1) or # 2 (HMH2-4) and 8 and A 16 mg formulation was made and used as a test capsule. The details of this Example 3d formulation and formulation containing formulation are disclosed in Table 16 below.

  The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 2 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 1, 2, 3, 6, 10, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules.

6 (n = 6) formulations HMH1 to HMH4 each.

The average dissolution data from the four sets of test capsules is summarized in Table 17 below. The dissolution release profiles for the two formulations are shown in FIG.

Example 3e:
In order to characterize the in vitro release of an abuse-resistant hydrocodone oral formulation across two different formulations, the following in vitro dissolution test was performed.

The abuse-resistant hydrocodone oral formulation used in this Example 3e was prepared using the following ingredients: Hydrocodone bitartrate (“HCB”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Gelucire 44/14 (Gattefose) (“GEL”); Cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). A formulation was prepared using the GMP manufacturing method (Process Scheme 9) of Example 1e above, then filled into a size 3 gelcap shell to produce a formulation, which was used as a test capsule. The details of this Example 3e formulation and formulation containing formulation are disclosed in Table 18 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 2 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 2, 3, 6, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. Each six (n = 6) formulations HCB1 and HCB2.Average dissolution data from two sets of test capsules are summarized in Table 19 below.

Example 3f:
In order to characterize the in vitro release of abuse-resistant oxymorphone oral formulations across several different formulations, the following in vitro dissolution test was performed.

The abuse-resistant oxymorphone oral formulation used in Example 3f was prepared using the following ingredients. Oxymorphone HCl (“OMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman) Chemicals) ("CAB"); and Gelucire 44/14 (Gattefose) ("GEL"). Formulations were made using a lab-scale manufacturing process and then filled into size # 1 gel capsules to make the formulations, which were used as test capsules. The details of the laboratory scale manufacturing process are as follows. SAIB and TA were mixed as a 1.5: 1 stock solution. The temperature was maintained at 60 ° C. ± 5 ° C. throughout the process experiment. The SAIB / TA stock solution was mixed for 15 minutes at 420 rpm. GEL was added and mixed into the blended mixture over 15 minutes at 600 rpm. Next, the IPM / BHT solution and the remaining IPM were added and the resulting mixture was treated at 600 rpm for 15 minutes, after which SiO ₂ was added and mixed at 550 rpm for 20 minutes. Next, homogenization was performed at 9,600 rpm for 5 minutes. Pre-screened CAB was added to the blended mixture and mixed at 960 rpm for 5 minutes, then increased to 1500 rpm for an additional 32 minutes to provide a placebo mixture. OMH was added to the preheated placebo mixture (60 ° C. ± 5 ° C.) and mixed with a spatula, followed by homogenization at 9,600 rpm for 5 minutes to produce the final formulation. The details of this Example 3f formulation and formulation containing formulation are disclosed in Table 20 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 1 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 1, 2, 3, 6, 10, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. Each of 4 (n = 4) formulations OMH1-OMH10. Average dissolution data from 10 sets of test capsules is summarized in Table 21 below and illustrated in FIGS. 10A and 10B.

Example 3g:
To characterize the in vitro release of an abuse-resistant amphetamine oral formulation across several different formulations, the following in vitro dissolution test was performed. The abuse-resistant amphetamine oral formulation used in Example 3g was prepared using the following ingredients. D-Amphetamine sulfate (Cambrex) (“AMP”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP , Ethanol wash ("CAB"); caprylocaproyl polyoxyglyceride ("Gattefose") ("CPG"); Gelucire 50/13 (Gattefosse) ("GEL"); and polyethylene glycol 8000 (Dow Chemical) ("PEG 8000"). Formulations were made using the GMP manufacturing process (process scheme 6 described in Example 1a above) and then filled into size # 1 gel capsules to make the formulations, which were used as test capsules. . The details of this Example 3g formulation and formulation containing formulation are disclosed in Tables 22 and 23 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 1 described above. However, the following points are different. That is, the sample time points were 1, 2, 3, 6, 8, 10, 12, 18, and 24 hours. Dissolution results were obtained for the following test capsules. Each of 8 (n = 8) formulations AMP1-AMP3. Average dissolution data from three sets of test capsules is summarized in Table 24 below and illustrated in FIG.

Example 3h:
In order to characterize the in vitro release of abuse-resistant methylphenidate oral formulations across several different formulations, the following in vitro dissolution test was performed.

The abuse-resistant methylphenidate oral formulation used in this Example 3h was prepared using the following ingredients: Methylphenidate (“MPH”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyltoluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP, ethanol wash ( Eastman Chemicals ("CAB"); Gelucire 50/13 (Gattefose) ("GEL"); and Miglyol 812 ("MIG"). Formulations were made using the manufacturing process described in Example 1a above (Process Scheme 6), then filled into a size # 3 gelatin capsule shell to make a formulation, which was used as a test capsule. . The details of this Example 3h formulation and formulation containing formulation are disclosed in Tables 25 and 26 below.

The dissolution test was performed using the dissolution test apparatus, reagents, and method of Method 1 described above. However, the following points are different. That is, the sample time points were 0.5 hours, 1, 1.5, 2, 3, 6, 9, 12, and 24 hours. Dissolution results were obtained for the following test capsules. Each 4 (n = 4) formulations MPH1 and MPH4 to MPH6 and each 8 (n = 8) formulations MPH2 and MPH3. Average dissolution data from 6 sets of test capsules are summarized in Table 27 below, Illustrated in FIGS. 12A and 12B.

Example 4: Analysis of the formulation (in vitro extraction and volatilization test procedure)
In order to evaluate the abuse-resistant performance of the formulation according to the present invention, the following in vitro extraction test was developed. In particular, the intentional abuse of controlled-release pharmaceutical formulations is often a simple extraction technique that can separate most or all of the active agent from a commercial controlled-release carrier system using common household solvents. Will be done by. Therefore, a group of in vitro extraction tests was developed to evaluate the abuse-resistant performance of formulations made according to the present invention.

Example 4a:
In order to evaluate the abuse-resistant performance of formulations made in accordance with the present invention, a group of tests to investigate the extraction of active agents from the formulations into the following commonly available household solvents was developed as follows. Vinegar (acetic acid), pH 2.5; cola soft drink, pH 2.5; sodium bicarbonate solution (sodium bicarbonate), pH 8.2; 100 proof ethanol (50% v / v); and vegetable oil. Test the formulations according to the invention against this group of normal household solvents, whether at ambient or “room” temperature (25 ° C.) or using preheated extraction solvent (heated to 60 ° C.). It is possible. In addition, it is also possible to perform exceptional stressing such as microwave pretreatment and freeze-fracturing pretreatment of the preparation before extraction into the solvent mentioned above.

  The materials and equipment used in the solvent extraction panel test of Example 4a are as follows. Standard laboratory equipment includes shaker (Jeo Tech Shaking Incubator, Model SI-600), hot water bath, hot plate, centrifuge, microwave oven, glass mortar and pestle, glass bottle with 250 mL cap, and Examples include a filtration unit (0.2 μm nylon membrane). Prepare the solvent reagents used in the extraction panel test as follows. Distilled water; 200 proof ethanol mixed in an equal part of distilled water to provide 100 proof ethanol solvent; distilled white vinegar with 5% acidity (Heinz); cola soft drink (Coke Cola Classic) ); Vegetable oil (canola); prepared by adding 527 g of baking soda to 2 liters of distilled water, mixing vigorously for about 1 hour, standing, and then filtering the supernatant using a 0.2 μm nylon membrane. Saturated solution of sodium bicarbonate (Arm & Hammer). Prior to the extraction test, the pH of vinegar, cola soft drink and saturated sodium bicarbonate solution was measured and recorded using a pH meter.

  The test procedure used for all solvents except vegetable oil solvent is as follows. 240 mL of each extraction solvent is placed in a separate extraction bottle. Next, add the formulation (if the formulation is a solid tablet, crush the formulation, then drop it into a solvent and if the formulation is a liquid capsule, cut the capsule to open the shell and The object is squeezed from the capsule into the solvent, and then the empty shell is dropped into the solvent). Start extraction on a shaker using a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5, 20, and 60 minutes. The sample is centrifuged at 10,000 rpm for 10 minutes and approximately 0.5 mL of the supernatant is transferred into an analytical HPLC vial (HP model 1200 or similar model). The extraction panel operation is then repeated when the extraction solution is pre-warmed in a 60 ° C. water bath. Next, the actual initial and final temperatures of the solvent solution are examined.

  The test procedure used for the vegetable oil solvent is as follows. Place 2 tablespoons of oil in an extraction bottle. Next, add the formulation (if the formulation is a solid tablet, crush the formulation, then drop it into a solvent and if the formulation is a liquid capsule, cut the capsule to open the shell and The object is squeezed from the capsule into the solvent, and then the empty shell is dropped into the solvent). Start extraction on a shaker using a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5, 15, 30, and 60 minutes. The sample is centrifuged at 10,000 rpm for 10 minutes and approximately 0.5 mL of the supernatant is transferred into an analytical HPLC vial (HP model 1200 or similar model).

  In an exceptional stress application test (microwave pretreatment and freeze-fracture pretreatment of the preparation before extraction into the solvent described above), the test procedure is as follows. For microwave stress analysis, the formulation is added to an empty extraction bottle (if the formulation is a solid tablet, it is crushed and then dropped into the bottle, and if the formulation is a liquid capsule, the capsule is cut. Open the shell and squeeze the liquid contents from the capsule into the bottle). Next, the power level is set to “high” (power = 90) and the extraction bottles (4 at a time) are microwaved for 2 minutes. Record the appearance of the formulation when removed from the microwave. Next, either 240 mL of distilled water or 240 mL of 100 proof ethanol solvent is added to the extraction bottle (evaluating extraction into water or ethanol). Start extraction on a shaker using a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5, 20, and 60 minutes. The sample is centrifuged at 10,000 rpm for 10 minutes and approximately 0.5 mL of the supernatant is transferred into an analytical HPLC vial (HP model 1200 or similar model). Next, after microwave treatment, equilibrate to room temperature (about 1.5 hours) and repeat this extraction procedure with the untested formulation.

  The preparations are stored as such overnight (18 hours) in a freezer at −80 ° C. for freeze fracture (physical and mechanical stress) analysis. The test sample was then removed from the freezer and held on dry ice until ready for grinding. The frozen formulation is then placed in a freezer bag (about 9 x 12 cm) and crushed by pressing immediately in a glass mortar and pestle. Next, the excess portion of the freezer bag (containing no formulation) is removed to provide a test article of about 9 × 9 cm, which is metered into the extraction bottle (using the remaining freezer bag). Next, either 240 mL of distilled water or 240 mL of 100 proof ethanol solvent is added to the extraction bottle (evaluating extraction into water or ethanol). Start extraction on a shaker using a constant speed of 150 rpm. Samples (1 mL) are withdrawn at 5, 20, and 60 minutes. The sample is centrifuged at 10,000 rpm for 10 minutes and approximately 0.5 mL of the supernatant is transferred into an analytical HPLC vial (HP model 1200 or similar model).

In order to evaluate the abuse-resistant performance of the pharmaceutical preparation made according to the present invention in this Example 4a, the extraction panel test described above was conducted to evaluate the formulation made according to Example 2 above. Specifically, the following ingredients were used to make a formulation for use in the extraction test. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Formulation is made using commercial scale manufacturing process scheme 4 (as described above) and then filled into a size 00 white impermeable gelcap shell to make a 40 mg formulation and tested. Used as a capsule. Details of the formulation of Example 4a are disclosed in Table 28 below.

  A controlled release tablet formulation as a control was procured as 40 mg OxyContin brand controlled release oxycodone tablets (Purdue Pharma, lot # W49E1, expiration date January 2009) and tested in the same test panel. Prior to extraction, the pH of the cola soft drink, vinegar, and saturated sodium bicarbonate solution at room temperature was found to be 2.49, 2.47, and 8.23, respectively.

  The overall kinetic behavior of oxycodone extraction from test capsules (made according to the present invention) and control (OxyContin) tablets at ambient temperature (RT) into a group of household solvents is shown in FIG. As can be seen, after 20 minutes of extraction point, the level of released oxycodone gradually converges in all groups. However, control (OxyContin) tablets tend to be immediate release (range 37-88%) compared to only 1.4-3.3% range for test capsules at 5 minutes . With the exception of extraction into saturated sodium bicarbonate solvent, oxycodone extracted from control tablets is quantitative at the extraction time point of 60 minutes (100% extraction). In contrast, the amount of oxycodone extracted from the test capsule is only about 20% for cola soft drinks and only 10% for other solvents at the 60 minute extraction time point.

  The overall kinetic behavior of oxycodone extraction from test capsules and control tablets at high temperature (5 ° C.) into a group of household solvents is shown in FIG. The temperature of the solvent before extraction was measured as 62 ° C. before extraction and 33 ° C. at the extraction time point of 60 minutes. As can be seen, the oxycodone extraction again converges gradually after the 20 minute extraction point, and the control tablets release immediately in all groups at the 5 minute time point (only 9 for the test capsule). There is a tendency of 64% to 96%) compared to 28%. In addition, with all solvents except saturated sodium bicarbonate solvent, oxycodone extraction from control tablets is quantitative with an extraction time point of 60 minutes (100% extraction). Conversely, the amount of oxycodone extracted from the test capsule is only about 42% for cola soft drinks and only 18-25% for other solvents at the 60 minute extraction time point.

The numerical results of the extraction panel test of this Example 4a including the results described above and the results shown in FIGS. 13 and 14 are reported in Table 29 below. As can be seen from the foregoing, it is possible to provide an abuse-resistant oral pharmaceutical formulation that exhibits excellent abuse-resistant performance over a group of solvent extraction tests using a formulation made according to the present invention.

  In order to further evaluate the abuse-resistant performance of the formulations according to the invention, the following in vitro volatilization test was developed. In particular, the intentional abuse of controlled release pharmaceutical formulations is another option, volatilization (in smoking or free base inhalation) that can release the active agent (in the immediate active form) from commercially available controlled release carrier systems. It can be implemented by a technique. Therefore, to evaluate (1) whether the oxycodone free base is more volatile than the salt (HCl) form and (2) whether the abuse-resistant formulation made in accordance with the present invention can prevent inhalation abuse due to volatilization. An in vitro volatilization test was developed.

For testing, 40 mg neat activator (free base form oxycodone, HCl salt form oxycodone), 40 mg test capsule (made as described above), and 40 mg SR control (controlled release oxycodone brand of OxyContin brand) Tablets) were weighed into petri dishes. A watch glass was attached as a cover to each Petri dish, and the covered test dish was placed on a hot plate (set to 10). After 30 seconds, each watch glass was replaced with a new watch glass and this process was repeated three times (acquiring four time points). Using Alpha Swab (TX 761), any residue deposited on the bottom of the test watch glass was removed with 40/60 ethanol /. Carefully transferred into a 005M HCl solution and the concentration of the oxycodone solution was measured by HPLC. The observations observed during the test were as follows. The neat base form active agent (oxycodone free base form) vaporizes / sublimates upon heating, but the test capsule and SR control tablet salt form active agent (oxycodone HCl) caused significant degradation and carbonization. It was notable that the vaporized drug (and solvent, if present) escaped during each watch glass change. This may be at least in part due to the low recovery shown in the following HPLC results. In addition, the presence of solvents and other excipients in the test capsules made it difficult to volatilize the oxycodone active agent and there was a particularly harmful odor that would be felt when the test capsules were volatilized. The HPLC results obtained in Example 4a are provided in Table 30 below.

  As can be seen from these results, the free base form (neat) of oxycodone volatilizes more easily than the HCl salt form of neat. However, when blocked in a controlled release system according to the present invention, oxycodone free base volatilizes to a much lesser extent. Thus, current volatility testing procedures may not provide a quantitative measure, but are useful in providing a relative measure of the degree to which a formulation is affected by abuse using such an approach.

Example 4b:
In order to characterize the in vitro abuse resistance performance of formulations prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. (A) Based on the effects of physical, chemical or mechanical stress and (b) via inhalation. Both series of test procedures are compared with commercial products. More specifically, three different production lots of 40 mg content abuse-resistant oxycodone oral formulations made with different purity grades of active agent (oxycodone) were used as test capsules. A 40 mg OxyContin brand (oxycodone HCl controlled release) tablet (Lot W28A1, Purdue Pharma LP) was used as a commercial comparison.

The abuse-resistant oxycodone oral formulation used in Example 4b was prepared using the following ingredients. Oxycodone base, micronized (“OXY”), grade 2 (specified to contain 0.25% (w / w) or less of 14-hydroxycodeinone (14-HC)) or grade 1 (0. Both grades are obtained from Norramco, Inc (Athens Georgia); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil) ®, Cabot Corp (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”) "); Triacetin USP (" T "); And cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Chemicals) (" CAB "). Formulations are made using commercial scale manufacturing methods (Process Scheme 4 or 5 described above) and then filled into size # 00 hard gelatin cap shell to make a 40 mg formulation, which is the test capsule. Used as. The detailed contents of this Example 4b formulation and formulation containing formulation are disclosed in Table 31 below.

  In vitro abuse resistance results were obtained with the following test capsules. Three 40 mg formulations (n = 3) (OXY1), containing grade 2 oxycodone and selected as exhibiting the fastest dissolution rate from the dissolution test described in Example 3 above, containing grade 2 oxycodone And three 40 mg formulations (n = 3) (OXY2) selected as exhibiting the slowest dissolution rate from the dissolution test described in Example 3 above, and three containing grade 1 oxycodone 40 mg formulation (n = 3) (OXY3). The commercial comparison was for three 40 mg OxyContin (SR control) tablets (n = 3).

With some exceptions described below, an in vitro abuse resistance test was performed using the same equipment, reagents and methods described above, substantially as in Example 4a above. Initially, the extraction of oxycodone active agents from test capsules and SR control tablets with four commercial beverages or normal household liquids / preparations was evaluated. The four selected solvents were selected based on their ubiquity and over the acidic and alkaline pH ranges. That is, vinegar (pH 2.5), cola soft drink (pH 2.4), hot tea (pH 4.6 to 5.1, range of 65 ° C. to 70 ° C.), and saturated sodium bicarbonate in water (pH 8.3 to 0.3). Range of 1). These selected solvents are readily available to potential abusers and constitute a non-toxic drinkable liquid that can be used to facilitate abuse. The test capsules were cut open to squeeze the liquid contents and ensure essential contact between the test solvent and the controlled release matrix. Prior to placement in the test jar, the SR control tablets were ground for 3 minutes using a mortar and pestle to break the controlled release matrix. Test capsules and treated SR control tablets were placed in test jars containing 240 mL of each solvent. Samples were taken at 5, 20, and 60 minutes by shaking the sealed jar vigorously at 100 rpm for 60 minutes with intermittent shaking. Solvent samples taken at each test interval were centrifuged and assayed by HPLC for oxycodone content. Extraction results are provided in Tables 32-35 below and FIG.

  As can be seen from these solvent extraction results, the test capsules were resistant to extraction into all test solvents for 60 minutes with agitation. After 5 minutes, less than 1% of oxycodone was extracted from the test capsules in cola, vinegar, and saturated sodium bicarbonate solution, whereas more than 90% of oxycodone in cola and vinegar and SR control tablets To about 75% in a saturated sodium bicarbonate solution. The maximum average extraction of oxycodone from the test capsules at 5 minutes (96% or 2.4 mg) occurred with hot tea. By comparison, extraction from SR control tablets into hot tea was 10 times (60% or 24 mg). Extraction of oxycodone from the test capsules increased slightly with all solvents over 60 minutes. In comparison, extraction from the SR control tablets occurred primarily within 5 minutes and remained fairly constant for the remainder of the study, strongly suggesting dose dumping. The maximum average amount of oxycodone extracted from the test capsule (15% or 6 mg) occurred in the hot tea after 60 minutes.

Next, the extraction of oxycodone active agent from the test capsules and SR control tablets with each of the six aqueous buffers ranging from pH 1 to pH 12 was evaluated. Specific buffer strengths were pH 1, pH 4, pH 6, pH 8, pH 10, and pH 12. The pH 1 buffer consisted of 0.1 N HCl, the pH 4 buffer consisted of 5 mM acetate, and the Ph6, 10 and 12 buffers consisted of 5 mM phosphate. The test capsules were cut open to squeeze the liquid contents and ensure essential contact between the test solvent and the controlled release matrix. Prior to placement in the test jar, the SR control tablets were ground for 3 minutes using a mortar and pestle to break the controlled release matrix. Test capsules and treated SR control tablets were placed in test jars containing 240 mL of each buffer. Samples were taken at 5, 20, and 60 minutes by shaking the sealed jar vigorously at 100 rpm for 60 minutes with intermittent shaking. Solvent samples taken at each test interval were centrifuged and assayed by HPLC for oxycodone content. The extraction results are provided in Tables 36 to 41 below and FIG.

  As can be seen from these buffer extraction results, all test capsules were resistant to extraction into all buffers over 60 minutes with agitation. After 5 minutes, less than 1% of the oxycodone activator was extracted into an aqueous buffer at pH 1-12, whereas more than 64% was extracted from the SR control tablets. It was observed that the amount of oxycodone extracted from the test capsules decreased with increasing pH. The maximum average oxycodone extraction from the test capsules into pH 1 buffer was 12% (4.8 mg) after 60 minutes, whereas the average oxycodone extraction (35.6 mg) from the SR control comparison was 89 %Met. Eventually, the extraction of oxycodone from the test capsules all into the buffer increased slightly with time, but a substantially complete dose dumping of oxycodone from the SR control tablet occurred within the first 5 minutes. (83% or 33.2 mg) remained fairly constant for the remainder of the study.

  Following this test, the extraction of oxycodone active agent from the test capsules and SR control tablets after physical disruption was examined. Specifically, the test capsules were cooled in dry ice for 16-20.5 hours to promote some tendency to freeze or brittleness of the formulation. Next, each cooling capsule was immediately placed in a folded plastic film and ground with a mortar and pestle for 3 minutes. Encapsulating the capsules in a folded plastic film during grinding prevented loss of test material due to the tendency of the product residue to stick to the mortar and pestle.

Each SR control tablet was also crushed and ground with a mortar and pestle. Three extraction solvents including water heated to 60-70 ° C. and ambient temperature (25 ° C.) water (0.1 N HCl) and 100 proof ethanol were used as extraction solvents. Physically disrupted samples were placed in test jars containing 240 mL of various solvents. Samples were taken at 5, 20, and 60 minutes by shaking the sealed jar vigorously at 100 rpm for 60 minutes with intermittent shaking. Solvent samples taken at each test interval were centrifuged and assayed by HPLC for oxycodone content. The extraction results are provided in Tables 42-45 below and FIG.

  During testing, it was noteworthy that the test capsules retained their fluid properties even at the low temperatures utilized in this test. As a result of crushing and grinding, the gelatin capsule shell breaks, but the formulation from the capsule remains as a high viscosity liquid. Thus, the formulations according to the present invention are believed to be less susceptible to the techniques available for crushing or crushing traditional controlled release formulations. As can be seen from the solvent extraction results, the test capsules were resistant to rapid release of oxycodone even after cooling, crushing, grinding and exposure to the extraction solvent. The amount of oxycodone extracted after 60 minutes ranged from 18% in water to 35% in 100 proof ethanol solution. Cumulative extraction was observed to increase gradually with time for all extraction solvents, but there was no evidence of rapid release or dose dumping. Therefore, these data suggest that the abuse-resistant formulation is highly resistant to extraction of the active ingredient (oxycodone) even after severe physical destruction. Furthermore, the resulting sticky liquid mass was found to be difficult to handle. In contrast, crushing and grinding SR control tablets in this test clearly impairs the performance of the solid controlled release matrix. In this connection, after only 5 minutes, 70-90% of the oxycodone dose was extracted into each extraction solvent, and then showed a slight increase.

  Next, the extraction of oxycodone from test capsules with SR and tablet SR was evaluated. The capsule was cut open and the contents were squeezed into the oil to ensure sufficient contact between the extracted oil and the test capsule formulation. Each SR control tablet was crushed and ground with a mortar and pestle for 3 minutes. The contents of the test capsule and the treated SR control tablet were placed in 10 mL of canola oil. This volume of oil was chosen because daily intake of larger amounts of oil could cause laxative effects and was therefore considered impractical. The sealed jar was shaken vigorously at 100 rpm for 60 minutes with intermittent shaking, and samples were taken at 30 and 60 minutes. Solvent samples taken at each test interval were centrifuged and assayed by HPLC for oxycodone content. The results of the test demonstrated that neither 1% of oxycodone was extracted from any formulation, so neither the test capsule nor the SR control tablet was extracted into the vegetable oil. These data suggest that such tests are probably not critical for formulations containing this active agent because canola oil is not a good solvent for oxycodone base or oxycodone HCl.

Following this test, the extraction of oxycodone from the test capsules after heating by microwave irradiation was investigated. Each test capsule was heated in a sample jar for 2 minutes with a home microwave oven at a high power setting (1250 watts). Due to microwave heating, the liquid contained in the test capsules dissolved and penetrated the gelatin capsule, and in many cases the heated liquid mass also caused the capsule to explode. A 240 mL volume of the next test solution was then added to each test jar, namely water (25 ° C.), 0.1 N HCl, and 100 proof alcohol solution. Samples were taken at 5, 20, and 60 minutes by shaking the sealed jar vigorously at 100 rpm for 60 minutes with intermittent shaking. Solvent samples taken at each test interval were centrifuged and assayed by HPLC for oxycodone content. Extraction results are provided in Tables 46-48 below and FIG.

  As can be seen from these extraction results, only 4% (1.6 mg) of the oxycodone dose was extracted from the microwave treated test capsules after 5 minutes extraction into each extraction liquid. After 60 minutes, only about 14-10% of the oxycodone dose was extracted in any test solution. These data indicate that the test capsules are resistant to rapid extraction or dose dumping of the active agent (oxycodone) into normal household fluids even after excessive heat stress.

Example 4c:
In order to characterize the ability of an abuse-resistant formulation prepared according to the present invention to be resistant to injection-based abuse forms, the following in vitro injection abuse abuse assessment was performed. In this context, the properties of an injectable suspension are defined as syringe inhalation and injectability. Syringe inhalation is related to the ability to draw a suspension into an empty syringe through a hypodermic needle, while injectability is directed to the ability to push the suspension out of a filled syringe through the hypodermic needle. Both properties depend on the viscosity and physical properties of the test formulation.

In the test, placebo (no active agent) formulations were examined for syringe inhalation and injectability to assess resistance to abuse by injection. The placebo formulation used in Example 4c was prepared using the following ingredients: Isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”) Sucrose acetate isobutyrate (Eastman Chemicals), ("SAIB"); triacetin USP ("TA"); and cellulose acetate butyrate, grade 381-20 BP, ethanol wash ("CAB") . A placebo formulation was made using a commercial scale manufacturing method (process scheme 4 or 5 described above) and filled into a gelatin capsule shell (size # 00) to make a test capsule. Details of the placebo formulation used in this Example 4c are disclosed in Table 49 below.

  The test equipment and test equipment used in this test are syringe barrel (Becton Dickinson (BD) 3 mL disposable syringe with Leur-Lok tip), hypodermic needle (BD (305136) PrecisionGlide needle 27G1.25, BD (305125) PrecisionGlide needle 25G1, BD (305190) PrecisionGlide needle IV 1.5, 21G, BD (305185) PrecisionGlide needle Fill 1.5, 18G), and Instron 5542 controlled by BLUEHILL software. Included a load frame.

  Initially, syringe inhalation was evaluated in two ways. First, by puncturing the hypodermic needle into the capsule shell and attempting to aspirate the placebo formulation from the test capsule, and secondly, by cutting the formulation into the syringe and Syringe inhalation using a placebo formulation equilibrated to room temperature (25 ° C) by attempting to squeeze the formulation from the opened capsule into the back end of the syringe barrel (ie, with the plunger pulled out) Sex analysis was performed. Both of these approaches can be used by drug abusers. Any placebo formulation mass that was successfully aspirated or filled into the syringe was quantified and recorded.

  Injectability was examined by pushing the plunger of a prefilled syringe using an Instron loading frame device in an attempt to deliver a placebo formulation. The force required to successfully inject the placebo formulation or the force at which the breakage occurred was recorded by the device. A disposable syringe barrel was filled with approximately 1 g of the placebo formulation (range 0.64 to 1.14 g). To minimize variability in injectability analysis, trapped air was removed by applying a vacuum while pressing the plunger. Tests were conducted with two sets of placebo formulations equilibrated to either 25 ° C or 37 ° C. 18, 21, 25, and 27 gauge size needles were connected to pre-filled syringe barrels by Luer-Lok fittings. Three different crosshead speeds (i.e., plunger pressing speed) were examined for each needle gauge. Based on the typical infusion rates demonstrated for parenteral administration, crosshead speeds of 150 mm / min, 550 mm / min, and 950 mm / min were selected. Three samples were tested at each condition setting.

  The results of this abuse resistance test were as follows. Syringe inhalation: The placebo formulation could not be aspirated into the syringe using the largest diameter needle (18 gauge) due to the high viscosity and thixotropy of the formulation. As a result, it was not examined using smaller diameter needles (21, 25, and 27 gauge). The placebo formulation was squeezed at room temperature from the opened capsule into the rear end of the tared syringe barrel. The weight successfully transferred into each of the five syringes was recorded. An average weight of 0.42 g (range 0.22-0.50 g, average 54%, range 28-64%) was transferred from the test capsule. Therefore, syringe inhalation was not achieved with any gauge needle in the test. In this connection, the quantitative transfer of the capsule contents into the syringe barrel was hampered by the high viscosity and cohesive properties of the placebo formulation.

  Injectability of the placebo formulation at room temperature was only achieved using an 18 gauge needle with the slowest crosshead speed of 150 mm / min. At 37 ° C., the formulation is less viscous and injectability is achieved in all three samples using an 18 gauge needle at a speed of 150 mm / min and using an 18 gauge needle at a speed of 550 mm / min. Achieved in two of the three samples. Using 21, 25, and 27 gauge needles, either load failure or mechanical failure occurred at both test temperatures and at all three crosshead speeds.

  Injectability of the placebo formulation at room temperature was only achieved using an 18 gauge needle with the slowest crosshead speed of 150 mm / min. At 37 ° C., the formulation is less viscous and injectability is achieved in all three samples using an 18 gauge needle at a speed of 150 mm / min and using an 18 gauge needle at a speed of 550 mm / min. Achieved in two of the three samples. Either load failure or mechanical failure occurred at both test temperatures using 21, 25, and 27 gauge needles and at all three crosshead speeds.

The following information was taken into account when interpreting the results of each test. The disposable disposable syringe is defined to withstand an internal barrel pressure of 45 lb _f / in ² for 30 seconds (corresponding to a pressure of 18.2 N acting on the plunger rod). In a 3 mL (ID = 0.34 in.) Disposable syringe barrel, 1 lb _f / in ² is generated in the syringe barrel when 1 lb _f is added to the plunger rod. The average pinch force (Palmer Pinch) applied by healthy men is 23-23.4 lb _f .

In this test, injectability was evaluated using the following failure mode. A triple failure test set was used to conclude the overall failure of the test with respect to failure of at least one sample. If the syringe barrel bends due to excessive internal pressure, the plunger barrel breaks and the fluid results in bypassing the plunger stopper. This event is determined by observing the sample or is demonstrated by a load force profile that decays with Instron tracking. If the needle separates from the syringe barrel due to excessive internal pressure, a Leur-Lok bond breakage occurs. This failure event is determined by observing incomplete sample delivery from the syringe, or is demonstrated by a sudden drop in the load force profile with Instron tracking. If the force required to successfully deliver fluid from the syringe exceeds the healthy male Palmer pinch force of 23.4 lb _f (104 N), excessive force failure occurs. This event is evident from Instron tracking.

A successful injection of the placebo formulation required equivalent performance for all three test samples. The criteria for success was delivery of at least 80% of the pre-filled initial mass. In addition, Instron tracking must present a consistent profile of the force applied during plunger movement. Even when the force profile remained consistent during the test and caused the delivery of the placebo mass from the syringe, more than 62N force was required to achieve delivery. This magnitude of force results in a barrel pressure of 153 lb _f / in ² that is 340% of the pressure determined by the manufacturer.

  From these assessment results for both syringe inhalation and injectability, an abuse-resistant controlled release formulation prepared in accordance with the present invention can be delivered using a conventional hypodermic needle as available to drug abusers. It is demonstrated that there is no possibility. This is believed to be due to the combination of the preferred syringe pressure limit, human force limit, and the high viscosity of the formulation.

Example 4d:
In order to characterize the ability of an abuse-resistant formulation prepared according to the present invention to tolerate forms of abuse based on inhalation, the following in vitro inhalation abuse resistance evaluation was performed. More specifically, two different production lots of 40 mg content abuse-resistant oxycodone oral formulations made with different purity grades of active agent (oxycodone) were used as test capsules.

A 40 mg content of OxyContin brand (oxycodone HCl controlled release) tablets (Lot W28A1, Purdue Pharma LP) (SR control) was used as a commercial comparison.

The abuse-resistant oxycodone oral formulation used in Example 4d was prepared using the following ingredients: Oxycodone base, micronized (“OXY”), grade 2 (specified to contain 0.25% (w / w) or less of 14-hydroxycodeinone (14-HC)) or grade 1 (0. Both grades are obtained from Norramco, Inc (Athens Georgia); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil) ®, Cabot Corp (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”) "); Triacetin USP (" T "); And cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Chemicals) (" CAB "). Formulations are made using commercial scale manufacturing methods (Process Scheme 4 or 5 described above) and then filled into size # 00 hard gelatin cap shell to make a 40 mg formulation, which is the test capsule. Used as. The details of this Example 4d formulation and formulation containing formulation are disclosed in Table 50 below.

  In the in vitro inhalation abuse resistance assessment, the following test capsules were used: three 40 mg formulations containing grade 2 oxycodone (n = 3) (OXY1), three 40 mg formulations containing grade 1 oxycodone ( n = 3) (OXY2) was used. The commercial comparison was for three 40 mg SR control tablets (n = 3).

  To examine the potential for abuse of the test capsule by inhalation, a volatilization test was performed. Initially, thermogravimetric analysis was used to determine the weight loss of oxycodone base and oxycodone HCl in order to determine the proper temperature for conducting the volatilization test. The oxycodone base was subjected to a temperature condition (30 to 350 ° C.) that gradually increased at a ramp rate of 20 ° C./min. Vaporization occurred above 200 ° C and ended at 310 ° C. Vaporization of oxycodone HCl (28-400 ° C.) was similar to that of the free base up to about 300 ° C., followed by significant decomposition of the salt form. Based on these observations, a temperature of 280 ° C. was selected for this test. This temperature is above the melting point of oxycodone (to ensure proper drug vaporization) and below 300 ° C. (to limit decomposition of the salt form). A maximum exposure time of 10 minutes was selected based on observations from preliminary tests. Beyond that time point, little additional oxycodone was recovered.

  The volatile system was designed to control the temperature applied to the test sample. The system consisted of an aluminum block and a temperature monitoring thermocouple was attached to the hot plate. Each aluminum block contains four holes for placing a glass sample pan. Each sample pan was capped with a pre-cooled aluminum cover holding a frozen gel pack on top to facilitate condensation of the volatilized oxycodone. Three dishes contained the test sample in each test, while the fourth dish served as a blank control. Two lots of test capsules and a single lot of SR control tablets were examined in triplicate. Each test capsule was cut open, the liquid contents were squeezed into the sample pan, and each SR control tablet was ground with a mortar and pestle and then transferred to the sample pan. The aluminum block was stabilized at 280 ° C. before the start of the test. The covers were swabbed at 3, 5, and 10 minutes to collect oxycodone and the samples were analyzed using HPLC. The results of the volatilization test were as follows. Average oxycodone recovery after volatilization at 280 ° C. (data in the form of average oxycodone recovered with standard deviation (SD) reported as% of initial dose): Test capsule = 2% at 3 minutes (0.8) 4% (2.1) at 5 minutes and 12% (2.1) at 10 minutes. SR control tablet = 12% (2) at 3 minutes, 11% (2) at 5 minutes, and 10% (2) at 10 minutes. These data are shown in FIG.

  As can be seen from these results, 3 SR control tablets were volatilized at 280 ° C for 3 minutes, resulting in an average oxycodone release of 12% of the total drug mass, while 6 test capsule tablets were 280 ° C. For 3 minutes, resulting in an average oxycodone release of only 2% of the total drug mass. However, after 10 minutes, approximately equal amounts of oxycodone volatilized from each formulation (10% compared to 12% release). Of note during observations during the study, the vaporization of oxycodone from the test capsules was accompanied by the release of smoke that appeared to be unpleasant (irritating that was found to irritate the respiratory tract and throat when inhaled) (Based on volatilization of placebo test capsule formulation that caused nose-white smoke generation). Vaporization of oxycodone from the SR control tablet exhibited significant charring. The low level of oxycodone released from the test capsules during initial heating in this volatilization test with unpleasant smoke generation suggests that the abuse-resistant formulation according to the present invention suppresses abuse by inhalation. .

Example 4e:
In order to characterize the in vitro abuse resistance performance of oral preparations of oxycodone prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, the abuse-resistant oxycodone oral formulation was evaluated over a series of formulations for resistance to extraction into ethanol solution. The abuse-resistant oxycodone oral formulation used in Example 4e was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); sodium lauryl sulfate (" SLS "); Labrafil M2125 CS (“LAB”); Gelucire 44/14 (Gattefose) (“GEL”); and cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman Che) icals) ( "CAB"). Formulations are made using a commercial scale manufacturing method (process scheme 4 or 5 as described above) and then filled into size # 00 hard gelatin cap shell to make an 80 mg formulation, which is the test capsule. Used as. The detailed contents of this Example 4e formulation and formulation containing formulation are disclosed in Table 51 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. 6 (n = 6) formulations OXY1 to OXY9 each.

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hours, 1, 2, and 3 hours. The results of the extraction test are provided in Table 52 below.

Example 4f:
In order to characterize the in vitro abuse resistance performance of hydromorphone oral formulations prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, the abuse-resistant hydromorphone oral formulation was evaluated over a series of contents (8 mg and 16 mg contents) and over a series of formulations for resistance to extraction into ethanol solution. The abuse-resistant hydromorphone oral formulation used in Example 4f was prepared using the following ingredients: Hydromorphone HCl (“HMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate Grade 381-20 BP, Eastman Chemicals ("CAB"). A formulation was made using the GMP manufacturing method of Example 1d above (process scheme 8), then filled into a gel cap shell of size # 1 (HMH1) or # 2 (HMH2-4) and 8 and A 16 mg formulation was made and used as a test capsule. The detailed contents of the formulation used in Example 4f are disclosed in Table 53 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. 6 16 mg formulations, formulation HMH1 (n = 6); 6 16 mg formulations, formulation HMH2 (n = 6); 6 16 mg formulations, formulation HMH3 (n = 6); and 6 8 mg Formulation, formulation HMH4 (n = 6).

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hours, 1, 2, and 3 hours. Extraction test results are provided in Table 54 below.

Example 4g:
In order to characterize the in vitro abuse resistance performance of hydrocodone oral preparations prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, the abuse-resistant hydrocodone oral formulation was evaluated over a series of contents (15 mg and 75 mg contents) and over a series of formulations for resistance to extraction into ethanol solution. The abuse-resistant hydrocodone oral formulation used in this Example 4g was prepared using the following ingredients: Hydrocodone bitartrate (“HCB”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Gelucire 44/14 (Gattefose) (“GEL”); Cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). A formulation was prepared using the GMP manufacturing method (Process Scheme 9) of Example 1e above, then filled into a size 3 gelcap shell to produce a formulation, which was used as a test capsule. The details of this Example 4g formulation and formulation containing formulation are disclosed in Table 55 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. Six 15 mg formulations, formulation HCB1 (n = 6); and six 75 mg formulations, formulation HCB2 (n = 6).

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hour, 1 and 3 hours. The results of the extraction test are provided in Table 56 below.

Example 4h:
In order to characterize the in vitro abuse resistance performance of oral preparations of oxymorphone prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, the abuse-resistant oxymorphone oral formulation was evaluated over a series of formulations for resistance to extraction into ethanol solutions. The abuse-resistant oxymorphone oral formulation used in Example 4h was prepared using the following ingredients. Oxymorphone HCl (“OMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP, ethanol wash (Eastman) Chemicals) ("CAB"); and Gelucire 44/14 (Gattefose) ("GEL"). Formulations were made using the laboratory scale manufacturing process described in Example 3f above, then filled into size # 1 gel capsules to make the formulations, which were used as test capsules. The detailed contents of this Example 4h formulation and formulation containing formulation are disclosed in Table 57 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. Three (n = 3) formulations OMH1 to OMH10 each.

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hour, 1 and 3 hours. The results of the extraction test are provided in Table 58 below.

Example 4i:
In order to characterize the in vitro abuse resistance performance of oral amphetamine formulations prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, the abuse-resistant amphetamine oral formulation was evaluated over a series of formulations for resistance to extraction into ethanol solution. The abuse-resistant amphetamine oral formulation used in Example 4i was prepared using the following ingredients. D-Amphetamine sulfate (Cambrex) (“AMP”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP , Ethanol wash ("CAB"); caprylocaproyl polyoxyglyceride ("Gattefose") ("CPG"); Gelucire 50/13 (Gattefosse) ("GEL"); and polyethylene glycol 8000 (Dow Chemical) ("PEG 8000"). Formulations were made using the GMP manufacturing process (process scheme 6 described in Example 1a above) and then filled into size # 1 gel capsules to make the formulations, which were used as test capsules. . The detailed contents of this Example 4i formulation and formulation containing formulation are disclosed in Tables 59 and 60 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. Three (n = 3) formulations AMP1 to AMP3 each.

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hour and 3 hours. The results of the extraction test are provided in Table 61 below.

Example 4j:
In order to characterize the in vitro abuse resistance performance of a methylphenidate oral formulation prepared according to the present invention, the following in vitro abuse resistance evaluation was performed. More specifically, abuse-resistant methylphenidate oral formulations were evaluated across a range of formulations for resistance to extraction into ethanol solutions. The abuse-resistant methylphenidate oral formulation used in Example 4j was prepared using the following ingredients: Methylphenidate (“MPH”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyltoluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP, ethanol wash ( Eastman Chemicals ("CAB"); Gelucire 50/13 (Gattefose) ("GEL"); and Miglyol 812 ("MIG"). Formulations were made using the manufacturing process described in Example 1a above (Process Scheme 6), then filled into a size # 3 gelatin capsule shell to make a formulation, which was used as a test capsule. . The details of this Example 4j formulation and formulation containing formulation are disclosed in Tables 62 and 63 below.

  The following test capsules were used in the in vitro abuse resistance evaluation. Three (n = 3) formulations MPH1 to MPH6 each.

With the following exceptions, an ethanol solution extraction test was conducted in substantially the same manner as in Example 4a above, using the same equipment, reagents and methods as described above. The extraction solution was 60 mL of 80 proof ethanol (40%). In addition, sampling was performed at time = 0.5 hr and 3 hours. The results of the extraction test are provided in Table 64 below.

Example 5: Formulation Analysis (Formulation Viscosity Test Procedure)
In order to evaluate the viscosity of formulations prepared according to the present invention, the following viscosity test was developed. With these tests it is possible to achieve both standard and dynamic viscosity measurements. The viscosity test apparatus used in the method described in this Example 5 is a Brookfield digital rheometer. The two specific models used are the following: JPII with programmable / digital controller Model 9112, Model HBDV-III + CP, and JPI with immersion circulator Model 1122S, Model LVDV-III + CP. A CPE spindle 52 was used in both rheometer models. In dynamic rheology, the dynamic rheology of the formulation can be measured using an Anton Paar Physica MCR301 rheometer (Anton Paar USA, Ashland, VA) equipped with a temperature control module and a vibration strain control module.

  The viscosity test method can provide sample formulations in two different forms, either bulk formulations or single formulations (eg, gelatin capsules). For bulk formulation testing, 0.5 mL of formulation is injected directly into the rheometer cup. When testing the formulation, two gelatin capsules are required for each measurement. Open the gelatin capsule using a razor blade and a clean cutting surface. Next, the contents are squeezed and placed in a rheometer cup.

  Typical temperature conditions for the viscosity test method are 37 ° C for most single point measurements and 30 ° C, 40 ° C, 50 ° C, and 60 ° C for temperature profiles. Measurements were taken at two different shear rates for each sample. That is, the first is low shear and the rpm setting is selected to provide a torque value of 10-15%, the second is high shear and the rpm setting is 20-90. % Torque value is selected.

  Viscometric data collection is performed using standard techniques. For example, the Brookfield digital rheometer data report screen automatically displays rotational speed, spindle number, torque value (%), and viscosity for manual recording.

  Finally, it is possible to measure the complex viscosity of a formulation sample using various vibrational strains in a linear viscoelastic regime. In this case, it is possible to obtain the intrinsic complex viscosity of the stationary sample formulation based on mathematical curve fitting of empirical data points. The advantage of dynamic vibration experiments is that the sample formulation material is probed without destroying the material microstructure.

Example 6: In vitro / in vivo correlation (IVIVC) analysis of formulations The concept of in vitro / in vivo correlation (IVIVC) determination for oral long-term (controlled, sustained) release formulations is a well-known concept used by pharmaceutical scientists And enables the prediction of expected bioavailability and other pharmacological performance characteristics from in vitro dissolution profile characteristics. Information and guidance regarding IVIVC determinations can be found on the US FDA website and on other pharmacological reference sites. In order to evaluate and characterize the abuse-resistant formulation prepared in accordance with the present invention, the following IVIVC analysis was performed.

Example 6a:
By developing a conversion function in accordance with FDA Guideline for Extended Release (ER) dosage forms, the second dissolution method (method 2) described in Example 3 above (controlled release of the controlled release formulation according to the present invention) In vitro controlled release profiles of candidate formulations obtained using (optimized to evaluate performance) and in vivo blood obtained with the pharmacokinetic human clinical follow-up described herein below The following IVIVC analysis was used to establish a correlation with medium concentration data.

More specifically, the rate or extent of active agent dissolution observed in the in vitro dissolution test described in Example 3 above, and the actual in vivo pharmacokinetic performance observed (measured plasma drug A predictive mathematical model describing the relationship between the concentration or amount of active agent absorbed when administered to a human subject, eg, Examples 7 and 8 below, was developed using the abuse-resistant oxycodone prepared according to the present invention. Developed for oral formulations. Specifically, the following ingredients were used to make a formulation for use in testing. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). The formulation was filled into a gel cap to provide a suitable formulation (test capsule).

Ideally, the plasma concentration of oxycodone after administration of the test capsule would have been obtained from a single cross-over study in a group of volunteers. However, since data were obtained from different trials, all pharmacokinetic, deconvolution, and convolution analyzes were performed using the mean plasma concentration data from each trial. The in vitro data of the test capsule was fit to the Weibull function.

Where τ is the time required to dissolve 62.5% of the dose and β is the slope parameter. This was the simplest model consistent with the extreme dissolution of the slow and fast dissolution lot data.

  Mean plasma concentration-time data were consistent with a two-compartment model with first-order absorption and excretion. The model was parameterized using the absorption rate constant K01, the discharge rate constant K10, the distribution rate constants K12 and K21, and the volume Vc / F of the central compartment (compartment 1). Where F is bioavailability.

  Parameters “A” and “B” were normalized to dose and parameters were derived from secondary parameters. Using the parameters estimated from the solution, the mean plasma oxycodone concentration-time data of the test capsule lots was deconvoluted to give an estimate of the in vivo release rate.

  This analysis suggested that the dissolution profile of test capsule lots with values of τ in the Weibull function in the range of 6-14 h should provide an equivalent in vivo plasma concentration-time profile. Although the dissolution profile appears to slow over time, there is no clear effect on in vivo bioavailability. Specifically, the observed values of τ in the Weibull function (obtained over a period of more than one year) are 6.09 ± 0.12, 10.1 ± 0.08, 12.8 ± 0.19, 11. 6 ± 0.11 and 14.1 ± 0.21.

Example 6b:
By developing a conversion equation between the cumulative percentage of dose supply into the in vivo circulation (cumulative supply) and the cumulative percentage of dose released in vitro (cumulative release), the following analysis was used: Established correlation between in vitro controlled release profile of d-amphetamine from candidate abuse-resistant formulations and in vivo blood concentration data obtained in the pharmacokinetic human clinical studies described herein below did. Given a human plasma concentration-time profile of d-amphetamine derived from oral administration of an abuse-resistant formulation prepared according to the present invention, it is possible to obtain a cumulative feeding profile via deconvolution. For this purpose, it is necessary to have a unit impulse response function (UIR). This can be derived from compartmental pharmacokinetic analysis of human concentration-time data after intravenous bolus administration of d-amphetamine. Such data was obtained from published literature.

In this case, A = 98.3 ± 6.01, B = 28.2 ± 0.56, α = 9.65 ± 0.64, and β = 6.31 × 10 ⁻² ± 3.78 × 10 ^{− 3} .

WinNonLin 5.2 (Pharsight Corp., Mountain View, Calif.) Deconvolved the mean plasma profile for the three abuse-resistant amphetamine oral formulations to determine the cumulative percentage of dose absorbed in vivo. Obtained. A cumulative percent value of the dose released in vitro was measured using a second lysis method at the same time point as the human concentration-time profile. By plotting the in vitro emission against the in vivo supply, it is possible to find a conversion equation by least squares fitting of a third order polynomial. For example,

In this case, y is% in vitro release, x is% in vivo supply, and a = 2 × 10 ⁻⁴ , b = 2.54 × 10 ⁻² , c = 1.53, and d = 36 It is. It is possible to find other functional forms that provide a good fit. With such a conversion equation, it is possible to calculate the in vitro release profile necessary to generate the desired in vivo concentration-time profile.

  In addition, by calculating the in vivo supply from the in vitro release, either analytical or numerical, by inverting the transformation equation, and then convolving the supply with the UIR, a specific in vitro It is possible to predict a human concentration-time profile for d-amphetamine obtained from the release profile.

Example 7: In vivo analysis of formulations (human clinical trials, pharmacokinetic studies)
In order to evaluate the in vivo controlled release performance of an abuse-resistant oxycodone oral formulation prepared according to the present invention, the following human clinical follow-up was performed. In all the tests described below, plasma samples were analyzed for oxycodone, noroxycodone, and oxymorphone from CEDRA Corporation using a validated LC-MS-MS procedure. The validity of the method was verified in the range of 0.250 to 125 ng / mL for oxycodone, 0.500 to 250 ng / mL for noroxycodone, and 0.0500 to 25.0 ng / mL for oxymorphone. Data were analyzed by the non-compartment method in WinNonlin. For data summaries and descriptive statistics, concentration-time data below the limit of quantification (BLQ) was treated as zero (0.00 ng / mL). In the pharmacokinetic analysis, the BLQ concentration from time zero to the time at which the first quantifiable concentration was observed was treated as zero, and the embedded and / or terminal BLQ concentrations were treated as “missing”.

The abuse-resistant oxycodone oral formulation used in the study was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Formulations are made using commercial scale manufacturing methods (process scheme 4 or 5 described above) and then filled into size 00 white opaque gel cap shells to 5, 10, 20, 30, and A 40 mg formulation was made and used as a test capsule. Detailed contents of the formulations used in the tests of Examples 7a-7f and formulations containing the formulations are disclosed in Tables 65 and 66 below.

Example 7a:
Two abuse-resistant oxycodone formulations prepared according to the present invention and used to supply clinical trials, ie, formulations made using the method of Process Scheme 4 (see Example 2) vs. Process Scheme 5 In order to demonstrate bioequivalence of the formulation made using the method (see Example 2), the next human clinical trial was a single center, two-way cross-registration PK trial. This test was conducted with 48 healthy adult male and adult female volunteers (fed state). The formulation was provided as a 40 mg formulation test capsule and was prepared as described above. A single dose of each of the two formulations was administered at 96 hour intervals. To prevent opioid-related adverse events, subjects received naltrexone blockade.

The mean linear plasma concentration-time curve of oxycodone in the test is shown in FIG. Values for C _max and T _max based on mean plasma oxycodone concentration-time values are shown in Table 67 below, while mean (SD) oxycodone PK parameters from non-compartmental analysis of individual data in the study are shown in Table 68 below. Show.

As can be seen from the data, statistical analysis of the log-transformed C _max and AUC parameters demonstrated that the formulations produced by process schemes 4 and 5 were bioequivalent.

Example 7b:
To determine the rate and extent of absorption of 40 mg oxycodone base in an abuse-resistant oral formulation when administered in a fasted state, after ingestion of a low fat diet, and after ingestion of a high fat diet Was a single center, three-way crossed food effect PK study. The study was conducted with 48 healthy adult male and female volunteers. To prevent opioid-related adverse events, subjects received naltrexone blockade. All 46 subjects took the test formulation three times.

The mean linear and semi-log plasma oxycodone concentration-time curves from the test are shown in FIG. The C _max and T _max values based on mean plasma oxycodone concentration-time values are shown in Table 69 below, and the average oxycodone PK parameters from non-compartmental analysis of individual data in the study are shown in Table 70 below.

Log-transformed parameters were calculated for maximum exposure (C _max ) as well as total exposure (AUC _last and AUC _inf ) and used in statistical analysis. From a 90% confidence interval for the treatment ratio of three parameters using log-transformed data and two one-sided t-test procedures (see test vs.), for either low or high fat eating status It also suggests that the oxycodone exposure parameters are not within the 80-125% limit of the fasted state. Thus, food has a significant effect on both the rate and extent of absorption of oxycodone from a test abuse-resistant oral formulation, and oral bioavailability is ingested relative to administration of the formulation in the fasted state. Increased in state. There was no significant difference in the degree of exposure obtained from a low or high fed breakfast.

Example 7c:
To demonstrate the dose proportionality of 5, 10, 20, and 40 mg abuse-resistant oral formulations made according to the present invention and administered under single dose conditions, the following human clinical trial is a single center four-way It was a cross PK test. This test was conducted with 48 healthy adult male and adult female volunteers (fed state). To prevent opioid-related adverse events, subjects received naltrexone blockade. All 46 subjects took the test formulation four times. The mean linear and semi-log plasma oxycodone concentration-time curves obtained in the test are shown in FIG. The values for C _max and T _max from this Example 7c study based on mean plasma oxycodone concentration-time values are shown in Table 71 below. Average oxycodone PK parameters from non-compartmental analysis of individual data in this Example 7c test are shown in Table 72 and illustrated in FIG. As can be seen, statistical analysis suggests that the test formulation is dose proportional over the full range of doses.

Example 7d:
The next human clinical trial was a single center steady state PK trial. In this test, subjects ingested an abuse-resistant oral formulation (test capsule “OXY” containing 40 mg of oxycodone free base) at BID for 5 days 30 minutes after the start of the standardized breakfast test. To prevent opioid-related adverse events, subjects received naltrexone blockade. 36 subjects were enrolled in this study (22 men and 14 women). Two women and one man did not complete the study. 33 subjects were enrolled in the PK analysis.

The C _max and T _max values from this Example 7d study based on mean plasma oxycodone concentration-time values are shown in Table 74 below, and the mean oxycodone PK parameters from non-compartmental analysis of individual data in this study are Table 73 shows.

In this test, a significant gender effect was observed for C _max and T _max of oxycodone at steady state. However, the number of women who completed the study was small compared to the number of men who completed the study. ANOVA revealed that the power of the test was low. Accordingly, an alternative steady state test is described in Example 7e below. Based on a comparison of trough (pre-dose) plasma concentrations after the initial administration of the test formulation on days 1, 2, 3, 4, and 5 of the study, steady state concentrations of oxycodone were achieved on day 2 on average. It was done. After continuous administration of the 40 mg test formulation every 12 hours for 5 days, there was a significant increase in peak and overall systemic exposure to oxycodone, noroxycodone, and oxymorphone compared to exposure after the first dose. . Based on the log-transformed AUC0-12 value in this study, the percent ratio (day 5/1) was 168.46% for oxycodone, 306.24% for noroxycodone, and 192.33 for oxy and morphone. %Met. Oxycodone exposure in a dosing regimen in which a 40 mg test formulation is administered every 12 hours for 5 consecutive days based on the AUC _0-τ (Day 5) / AUC _0-12 (Day 1) ratio in individual subjects Increase 1.75 times. The accumulation ratios for noroxycodone and oxymorphone are 3.22 and 2.00, respectively.

Example 7e:
The next human clinical trial was a single center steady state PK trial. In this study, subjects took an oral abuse-resistant formulation (test capsule “OXY Test Capsule” or OXY containing 30 mg of oxycodone free base). To prevent opioid-related adverse events, subjects received naltrexone blockade. In addition, subjects ingested a meal before each administration of the test capsule (OXY). Forty-eight subjects were enrolled in this study (28 men and 20 women). Three subjects did not complete the study. Three other subjects also exhibited vomiting and as a final result 42 subjects completed the PK analysis (25 men and 17 women).

The C _max and T _max values from subjects (pooled men and women) who took the test capsule (OXY) based on mean plasma oxycodone concentration-time values are shown in Table 75 below and are non-compartmental for individual data Average oxycodone PK parameters from the analysis are shown in Table 76 below.

  Based on a comparison of trough (pre-dose) plasma concentrations after the first dose of test capsules on days 1, 2, 3, 4, and 5 of the study, steady state concentrations of oxycodone were achieved on day 2 on average It was done. After consecutive administration of 30 mg test capsules every 12 hours for 5 days, there was a significant increase in peak and overall systemic exposure to oxycodone, noroxycodone, and oxymorphone compared to exposure after the first dose. .

As a further analysis, the possibility of gender effects on the pharmacokinetic profile of the test capsule after a single dose of the test capsule and after a steady state multiple dose regimen of a test capsule administered for 5 days with BID is examined. The oxycodone pharmacokinetic parameters after a single dose of the test capsule are reported in Table 77 below, and the oxycodone pharmacokinetic parameters on the fifth day after multiple dose administration of the test capsule are reported in Table 78 below. To do. The average data for the male and female test groups from this gender analysis is reported in Table 75 above.

  As can be seen from these gender results, the peak oxycodone concentration in men occurs lower and earlier compared to the maximum oxycodone concentration in women. The higher plasma oxycodone concentrations observed in women were also reflected in AUC values.

Example 7f:
The next human clinical trial was a multicenter randomized, double-blind, placebo-controlled phase III trial in patients with moderate to severe chronic pain caused by hip or knee osteoarthritis. The study examined the efficacy and safety of abuse-resistant oral formulations (capsules containing oxycodone base and prepared according to the present invention) versus placebo over a 12-week double-blind treatment period.

The test abuse-resistant oral formulation used in the test was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Formulations are made using commercial scale manufacturing methods (process scheme 4 or 5 described above) and then filled into size 00 white opaque gel cap shells to 5, 10, 20, 30, and A 40 mg formulation was made and used as a test capsule. Details of the formulation of Example 7f are disclosed in Tables 79 and 80 below.

  In the study, patients who met eligibility criteria entered a 2-week open-label dosing phase. At this time, all patients received a test abuse-resistant oral formulation ranging from 5 mg BID to 20 mg BID. Patients who could tolerate the 20 mg BID test abuse-resistant oral formulation were randomized in a 1: 1 ratio to receive BID test abuse-resistant oral formulation or BID placebo. A total of 558 patients were enrolled and entered the open label dosing phase of the study, and a total of 412 patients were randomized. Dose adjustment was allowed over the first 4 weeks of the double-blind treatment period.

  Patients have a diary pain intensity score (PI) mean (baseline PI) of ≧ 5 over the last 2 days of the drug holiday, IVRS diary compliance is ≧ 75%, and patients continue If all selection / exclusion criteria were met, a two-week open label dosing period was entered. Over these 2 weeks, patient doses were made from a test abuse-resistant oral formulation of 5 mg BID to 20 mg BID.

  At the end of the open label dosing period, if the patient can tolerate a 20 mg BID test abuse-resistant oral formulation (no unacceptable adverse events) and IVRS diary compliance is ≧ 75%, the patient Enrolled in a double-blind placebo-controlled trial. A total of 412 patients received the test abuse-resistant oral formulation BID or placebo randomized at a 1: 1 ratio. Randomization was stratified by both baseline PI (<7.5 vs ≧ 7.5) and mean PI (<5 vs ≧ 5) over the last two days of the open label dose setting period. In this way, patients were divided as follows. That is, in Group A, 200 patients received the test abuse-resistant oral formulation at BID during a 12-week double-blind treatment period, and in Group B, 200 patients received a 12-week double-use treatment. A placebo was taken with BID during the blinded treatment period. The patient was dosed (increased or decreased) for analgesic effect over the first 4 weeks of the double-blind treatment period. At the end of 4 weeks, the dose was fixed for an additional 8 weeks.

The primary endpoint for this clinical trial in Example 7f was pain intensity between a test abuse-resistant oral formulation (test capsule) administered with BID and a placebo administered with BID over a 12-week treatment period ( AUC). Subjects who took the test capsules with BID showed a statistically significant decrease in their pain intensity-AUC compared to subjects who took placebo with BID. Thus, the study met its primary endpoint as defined in the prospective (p = 0.007). The primary endpoint results (analysis population: pain intensity over a 12-week double-blind period of the intentional treatment population-AUC) are reported in Table 81 below.

  Regarding the results shown in Table 81 described above, the intentional treatment population was randomized patients who took any study medication and received at least one randomized pain intensity measurement. In addition, the area under the curve (AUC) was calculated by the linear trapezoidal method using the change from the pain intensity score before randomization. The p values reported above were obtained from the ANCOVA model, which included treatment as the main effect and pain intensity before randomization as covariates.

  Secondary endpoints for clinical trials included pain intensity (changes in pain intensity on a weekly basis), analgesic quality, overall assessment, Short Form 12 Question Health Survey (SF-12), and Western Ontario and MacMaster Universities Institutes (October). WOMAC). In pain intensity results, the group that took the test capsule with BID always had a lower pain intensity score in each week during the 12-week clinical trial compared to the group that took placebo with BID (12 P = 0.024 in the week). In analgesic quality, the group that took the test capsule with BID showed a consistently greater improvement in the quality of analgesia each week during the 12-week clinical trial compared to the group that took placebo with BID. (P = 0.004 at the 12th week). In the overall evaluation, the group that took the test capsule with BID always showed a better overall evaluation at each week during the 12-week clinical trial compared to the group that took placebo with BID (p at week 12). = 0.007). In SF-12, the group that took the test capsule with BID had a physical factor score of SF-12 (p = 0.003 at 12 weeks) and SF− compared to the group that received placebo with BID. It had a higher value for the 12 mental component score (p = 0.055 at 12 weeks). In this case, a higher value corresponds to better health or function. In the WOMAC stiffness and physical function subscale, as expected, the group that received the test capsule with BID had a lower value compared to the group that received placebo with BID, but the difference was not significant. (Rigid subscale p = 0.366 at 12 weeks and physical function subscale p = 0.221 at 12 weeks). In the WOMAC pain subscale, the value (% change from baseline up to week 12) was significantly lower in the group receiving the test capsule with BID compared to the group receiving placebo with BID ( At week 12 p = 0.023). In this case, lower values correspond to better health or function. There were no drug-related safety issues in this study.

Example 7g:
Two lower contents used to evaluate the safety and pharmacokinetic behavior of three different high dose (80 mg content) abuse-resistant oxycodone formulations and in the tests of Examples 7a-7f above This human clinical trial was a single center randomized open label phase I trial to evaluate their performance against (40 mg) abuse-resistant oxycodone formulations (collectively OXY test capsules). .

The abuse-resistant oxycodone oral formulation used in Example 7g was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); sodium lauryl sulfate (" SLS "); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). Formulations are made using a commercial scale manufacturing method (process scheme 4 or 5 as described above) and then filled into size # 00 hard gelatin cap shell to make an 80 mg formulation, which is the test capsule. Used as. Detailed contents of the formulations are disclosed in Table 82 below.

  All four treatments start with a standard breakfast (8 ounces orange juice, 2 fried eggs, and 2 toasts with butter and jam) followed by an overnight fast for at least 10 hours 30 It was intended to be administered after a minute. The administration days were separated by a 3-day drug holiday. All subjects received naltrexone blockade to prevent opioid-related adverse events. Sixteen healthy male subjects were enrolled in the study and 15 completed the four treatment periods of the study. Plasma samples were analyzed for oxycodone using a validated LC-MS-MS procedure.

The results of pharmacokinetic analysis of the test results of Example 7g are shown in Table 83 below. In addition, the oral bioavailability of oxycodone for three 80 mg OXY test capsules versus 2 × 40 mg test capsules is shown in Table 84 below.

As can be seen from these results, the pharmacokinetic profiles of the three different high content test capsule formulations (OXY1 to OXY3) are comparable with respect to the peak oxycodone concentration observed from 4.35 to 4.68 hours. there were. The average C _max values for the three high content test capsule formulations were 29% to 46% lower than the average C _max after administration of the 2 × 40 mg test capsule (OXY10). Similarly, overall systemic exposure to oxycodone after administration of the three 80 mg test capsule formulations (OXY1 to OXY3) is greater (10% to 17%) than after administration of the 2 × 40 mg test capsule (OXY10). It was low. Finally, the relative bioavailability of the three 80 mg test capsule formulations (OXY1 to OXY3) based on AUC _last was very good (range 83.39% to 90.27%). Within> 80%).

Example 7h:
Two lower contents used to evaluate the safety and pharmacokinetic behavior of three different high dose (80 mg content) abuse-resistant oxycodone formulations and in the tests of Examples 7a-7f above This human clinical trial was a single center randomized open label phase I trial to evaluate their performance against (40 mg) abuse-resistant oxycodone formulations (collectively OXY test capsules). .

The abuse-resistant oxycodone oral formulation used in Example 7h was prepared using the following ingredients. Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); sodium lauryl sulfate (" SLS "); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). Formulations are made using a commercial scale manufacturing method (process scheme 4 or 5 as described above) and then filled into size # 00 hard gelatin cap shell to make an 80 mg formulation, which is the test capsule. Used as. The detailed contents of the formulation are disclosed in Table 85 below.

  All four treatments start with a standard breakfast (8 ounces orange juice, 2 fried eggs, and 2 toasts with butter and jam) followed by an overnight fast for at least 10 hours 30 It was intended to be administered after a minute. The administration days were separated by a 3-day drug holiday. All subjects received naltrexone blockade to prevent opioid-related adverse events. Sixteen healthy male subjects were enrolled in the study and completed the four treatment periods of the study. Plasma samples were analyzed for oxycodone using a validated LC-MS-MS procedure.

The results of pharmacokinetic analysis of the test results of Example 7h are shown in Table 86 below. In addition, the oral bioavailability of oxycodone for the three 80 mg OXY test capsules versus the 2 × 40 mg test capsules is shown in Table 87 below.

As can be seen from these results, the pharmacokinetic profiles of the three different high content test capsule formulations (OXY4 to OXY6) are comparable with respect to the peak oxycodone concentration observed between 4.44 and 4.55 hours. there were. The average C _max value of the three high content test capsule formulations was 17% to 28% lower than the average C _max after administration of the 2 × 40 mg test capsule (OXY10). However, overall systemic exposure to oxycodone after administration of the three 80 mg test capsule formulations (OXY4 to OXY6) was similar to that after administration of the 2 × 40 mg test capsule (OXY10). Finally, the relative bioavailability of the three 80 mg test capsule formulations (OXY4 to OXY6) based on AUC _last is almost complete, within the range of 98.74% to 105.88%. there were.

Example 8: In Vivo Abuse Tolerance Evaluation of Formulations Human drug preference studies demonstrated that reward increases with increasing rate of blood drug levels. In this case, the faster the drug flows into the blood, the better the rush or high state is provided. Savage et al. (2008) Addict Sci Clin Pract 4 (2): 4-25; Marsch et al. (2001) J Pharmacol Exp Ther 2001 299 (3): 1056-1065. In studies examining which properties of prescription opioids are more attractive for abuse purposes, the rate of appearance was supported as an important factor. Butler et al. (2006) Harm Reduct J 2006 3 : 5.

  Prescription drug abusers manipulate sustained release (“SR”) opioid formulations to dose dump (rapid release) the active agent to increase the rate of rise to achieve the desired high state. A common method of SR opioid abuse is chewing, crushing, and extraction followed by oral ingestion, nasal inhalation, or infusion of an opioid active agent to achieve a high state. An experienced carefree abuser may chew or crush the SR opioid and mix the engineered drug with alcohol. Inadvertent abusers are generally not drug-resistant, and dose dumping of opioid active agents can pose significant health risks and can result in accidental fatal overdose Even there.

  To examine the degree of dose dumping that occurs after physical manipulation of the currently available SR formulation of oxycodone (OxyContin, hereinafter “SR Control”), the following Phase I study was conducted in 5 healthy male volunteers It was. The lowest SR control dose (10 mg) was selected to optimize safety for volunteers. SR control tablets were crushed using a mortar and pestle, the engineered formulation was administered to volunteers with water or 40 proof alcohol, and a swallowed SR control tablet and a 10 mg dose of immediate release oxycodone formulation (Roxycodone, 2 × 5 mg).

The results of the test are provided in Table 88 below and illustrated in FIG.

  As can be seen from these results, when the SR control tablets were crushed and taken with water or alcohol, both the rate and extent of oxycodone absorption increased significantly (see FIG. 24).

Specifically, C _max increased from 6.82 ng / mL to 21.8 and 21.0 ng / mL for water or alcohol, respectively, relative to the SR control. This C _max was very similar to the C _max (18.9 ng / mL) obtained with the oxycodone IR tablet. Similarly, T _max decreased from 1.91 hours to 0.90 and 0.95 hours for water or alcohol after crushing, respectively. These T _max values were smaller than the T _max (1.35 hours) obtained with IR tablets.

  Total AUC is a pharmacological metric that represents the total amount of active agent absorbed. The AUC, or cumulative AUC, up to a certain time represents the amount of active agent absorbed up to that time, allowing an assessment of the rate of increase in exposure. This automatically corrects for differences in bioavailability and allows true comparisons between treatments and / or formulations. The fast absorption rate and the loss of controlled release mechanism after physical manipulation of the SR control tablet are evident from FIG. 24, which shows that the absorption rate is significantly increased.

Abuse index or AQ can be used as a way to express the attractiveness of a formulation / formulation to abuse. Webster LR (2007) Emerging opioid formations: abuse dependent or abuse resist? [Internet] Available from: http: www. emerging solutions sinpain. com / opencms / esp / communaries / index. html. AQ takes into account the observation that increasing C _max and decreasing T _max increases the attractiveness of certain formulations to abuse. It is expressed as the equation AQ = C _max / T _max . In this study, AQ was 3.57 for the SR control taken as-is and 14.0 for the immediate release tablet. After crushing the SR control with water or ethanol, the AQ of the SR control increased to 24.2 and 22.2, respectively, so the attractiveness of the SR control to abuse is greatly increased after physical manipulation. Is shown. AQ is a dose-dependent metric when C _max varies with dose. To facilitate comparison of this initial test with the subsequent in vivo abuse tolerance assessment of the abuse-resistant formulation according to the present invention at the 40 mg dose level, the equivalent AQ after dose adjustment is taken as is. SR control (40 mg) would be 14.3 and immediate release (40 mg) would be 56.0. After crushing the SR control with water or alcohol, the dose adjusted AQ will increase to 96.8 and 88.8, respectively.

  Therefore, in order to attempt to include a dose dumping effect or an immediate release effect, four Phase I in vivo abuse resistance evaluation tests were conducted and the abuse-resistant formulation according to the present invention using physical and chemical operations. Verified. All PKs described in this Example 8 as food effect studies with compatible formulations suggested that the rate and extent of absorption of oxycodone from the abuse-resistant formulation increased significantly when administered with food. In the study, test capsules were administered with food, while a reference oxycodone IR oral solution was administered under fasting conditions as a benchmark for the most rapid absorption of oxycodone. To minimize opioid-related side effects, subjects were pretreated with naltrexone in all PK studies.

  Plasma samples were analyzed for oxycodone, noroxycodone, and oxymorphone from CEDRA Corporation using a validated LC-MS-MS procedure in all in vivo abuse tolerance assessment tests described below. The validity of the method was verified in the range of 0.250 to 125 ng / mL for oxycodone, 0.500 to 250 ng / mL for noroxycodone, and 0.0500 to 25.0 ng / mL for oxymorphone. Data were analyzed by the non-compartment method in WinNonlin. For data summaries and descriptive statistics, concentration-time data below the limit of quantification (BLQ) was treated as zero (0.00 ng / mL). In the pharmacokinetic analysis, the BLQ concentration from time zero to the time at which the first quantifiable concentration was observed was treated as zero, and the embedded and / or terminal BLQ concentrations were treated as “missing”.

The abuse-resistant oxycodone oral formulation used in the study was prepared using the following ingredients: Oxycodone base, micronized (“OXY”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“ BHT "); hydroxyethylcellulose, NF (" HEC "); sucrose acetate isobutyrate (Eastman Chemicals) (" SAIB "); triacetin USP (" TA "); and cellulose acetate butyrate, grade 381-20 BP, Ethanol Wash (“CAB”). Formulations are made using commercial scale manufacturing methods (process scheme 4 or 5 described above) and then filled into size 00 white opaque gel cap shells to 5, 10, 20, 30, and A 40 mg formulation was made and used as an OXY test capsule. The details of the formulation of Example 8 and the formulation containing the formulation are disclosed in Tables 89 and 90 below.

Example 8a:
In order to evaluate the effect of physical disruption of a controlled release carrier system on the release of oxycodone active agent from an abuse-resistant oral formulation made according to the present invention, the following in vivo abuse abuse assessment test is a single Institutional four-way cross PK test. The test formulation (capsule containing 40 mg of oxycodone free base) (“OXY” test capsule) was administered as is or crushed with alcohol (feeding state). For comparison, oxycodone sustained release (SR) tablets (OxyContin brand sustained release oxycodone tablets, 40 mg, Purdue Pharma) (“SR Control”) were administered neat or crushed with alcohol (fasted state), Furthermore, a 40 mg oral solution of oxycodone HCl was administered (fasted state) as an immediate release control (“IR control”) to present a “worst scenario”. To prevent opioid-related adverse events, subjects received naltrexone blockade. Fifty subjects were enrolled in this study (27 men and 23 women). One man did not complete the study and the other man vomited within 12 hours of dosing. Forty-eight subjects were included in the PK analysis.

The mean linear and semi-logarithmic plasma oxycodone concentration-time curves obtained in this Example 8a test are shown in FIG. Values for C _max and T _max based on mean plasma oxycodone concentration-time values are shown in Table 91 below, and mean oxycodone PK parameters from non-compartmental analysis of individual data obtained in the test of Example 8a are shown in the table below. 92.

  As can be seen from these results, the following comparisons and conclusions can be derived.

1. Treatment A vs. B : (OXY test capsule 40 mg capsule (whole) vs. OXY test capsule 40 mg capsule (crushed), extracted with 40% ethanol). The 90% confidence interval for comparison of maximum exposure based on ln ( _Cmax ) was outside the required 80% -125% limit for oxycodone. _{C max} value of the crushed Test Capsules are approximately twice the _{C max} value of the raw test capsule, the maximum concentration is reached time _{(T max)} was faster better the crushed Test Capsules (2.97 Time vs. 5.15 hours). The 90% confidence interval for comparison of total systemic exposure based on ln (AUC _last ) and ln (AUC _inf ) was within the 80% to 125% limit allowed for oxycodone. Systemic exposure ln (AUC _0-2 ), ln (AUC _0-4 ), ln (AUC _0-6 ), and ln (AUC _0-12 ) at a faster stage and later stage exposure ln (AUC _0-24 ) and the 90% confidence interval for comparison was outside the 80% -125% limit for oxycodone. However, ln (AUC _0-48 ) was in the range of 80% to 125%.

2. Treatment D vs. E : (SR control (OxyContin) 40 mg tablet (crushed, extracted with 40% ethanol) vs. IR control (oxycodone HCl) oral solution 40 mg). The 90% confidence interval for comparison of SR control maximum exposure based on ln ( _Cmax ) was within the 80% -125% limit required for IR control (oxycodone). The 90% confidence interval for the comparison of total systemic exposure based on ln (AUC _last ) was within the 80% -125% limit allowed for the IR control. Comparison of earlier stage systemic exposure ln (AUC _0-4 ), ln (AUC _0-6 ), and ln (AUC _0-12 ) with later stage systemic exposure ln (AUC _0-24 ) The 90% confidence interval for was also within the 80% -125% limit for the IR control.

3. Treatment B vs. E : (OXY test capsule 40 mg capsule (crushed, extracted with 40% ethanol) vs. IR control (oxycodone HCl) oral solution 40 mg)). The 90% confidence interval for comparison of maximum exposure of crushed test capsules based on ln ( _Cmax ) was within the 80% -125% limit required for IR controls. The time to reach maximum concentration (T _max ) took longer for the crushed test capsule than for the IR control (2.97 hours vs. 0.97 hours). The 90% confidence interval for comparison of total systemic exposure based on ln (AUC _last ) and ln (AUC _inf ) was outside the acceptable 80% to 125% limit for IR controls. Early stage systemic exposure ln (AUC _0-2 ), ln (AUC _0-4 ), and ln (AUC _0-12 ), and later stage systemic exposure ln (AUC _0-24 ) and ln (AUC) _0-48 ) and the 90% confidence interval for comparison was also outside the 80% -125% limit for the IR control.

4). Treatment B vs. D : (OXY test capsule 40 mg capsule (crushed, extracted with 40% ethanol) vs. SR control 40 mg tablet (crushed, extracted with 40% ethanol)). The 90% confidence interval for comparison of maximum exposure for both OXY test capsules based on ln (C _max ) and SR control was within the 80% -125% limit required for IR control. However, the time to reach maximum concentration (T _max ) took twice as much as the SR control in the crushed test capsule (2.97 hours vs. 1.48 hours). The 90% confidence interval for the comparison of total systemic exposure based on ln (AUC _last ) was outside the acceptable 80% to 125% limit for the IR control. A 90% confidence interval for comparison of earlier systemic exposures ln (AUC _0-2 ), ln (AUC _0-4 ), and ln (AUC _0-6 ) of both test compositions is 80% required. It was within the limits of ˜125%. However, the median exposure ln (AUC _0-12 ) and later stages of systemic exposure ln (AUC _0-24 ) are outside the 80% -125% limit required for both compositions. Met.

5. Treatment C vs. D : (SR control 40 mg tablet (whole) vs. SR control 40 mg tablet (crushed, extracted with 40% ethanol)). The 90% confidence interval for the maximum exposure comparison based on ln (Cmax) was outside the 80% -125% limit required for the IR control. The time to reach maximum concentration (T _max ) was slightly longer for the intact SR control tablet (2.09 hours vs. 1.48 hours) relative to the SR control crushed tablets. The 90% confidence interval for comparison of later stage systemic exposure ln (AUC _0-24 ) and total systemic exposure based on ln (AUC _last ) was within the allowed 80% -125% limit. 90 for comparison of earlier stage of systemic exposure ln (AUC _0-2 ), ln (AUC _0-4 ), and ln (AUC _0-6 ) with the intermediate value of systemic exposure ln (AUC _0-12 ) The% confidence interval was outside the 80% -125% limit range.

In addition, a single dose of a 40 mg OXY test capsule (whole or crushed and extracted with 40% ethanol) and a whole or crushed 40 mg SR control tablet to be swallowed and extracted with 40% ethanol and a single 40 mg oxycodone solution IR control FIG. 27 shows the cumulative AUC (0 to 6 hours) of oxycodone after oral administration. As can be seen by referring to this figure and the PK results summarized in the table above, the C _{max of the} OXY test capsule increased from 43.8 ± 18.4 ng / mL to 78.8 ± 10.5 ng / mL. T _max decreased from 5.15 ± 2.24h to 2.97 ± 0.97h. However, even if the OXY test capsules were crushed and extracted with 40% ethanol, the extent of total absorption was not affected and absorption was not controlled by the IR control, regardless of the means used to operate the abuse-resistant formulation. (Average T _max was 0.97 ± 0.25 h). The absorption rate and peak exposure to oxycodone after crushing the OXY test capsule and extracting with 40% ethanol were also lower than the SR control tablet (T _max was 1.48, while C _max was 88. 4 ng / mL). It was noteworthy that 1 hour after administration, the plasma oxycodone concentration after crushing the OXY test capsule and extracting with 40% ethanol was lower than that after ingestion of the SR control. . For each test formulation, plasma oxycodone concentration vs. The cumulative percentage with respect to the lower total area of the time results is shown in FIG. As can be seen from the above, FIG. 28 shows that the exposure rate in the OXY test capsule after crushing and extraction (40% ethanol) is based on the cumulative percentage relative to the total AUC, and the SR control tablet and IR after crushing and extraction. It remains substantially lower than any of the control solutions, indicating a particularly significant difference in the initial time after administration.

  Finally, the AQ calculation in the test of Example 8A was as follows. OXY test capsule (as is), AQ = 8.5, and OXY test capsule (as crushed and extracted), AQ = 26.5; SR control (as is), AQ = 20.2, SR control (as crushed and extracted) , AQ = 59.7; and IR control, AQ = 94.3.

Example 8b:
In order to determine the release rate of oxycodone after dissolving the oral abuse-resistant test preparation (capsule containing 40 mg of oxycodone free base, “OXY” test capsule) in the buccal oral cavity of healthy volunteers, the following in vivo resistance The abuse assessment test was a single center, three-way cross PK test. Comparison of 40 mg test formulation administered as is (fed state) with 40 mg oral solution of immediate release (IR) oxycodone HCl (“IR control”) (fasted state) to present a “worst scenario” To do so, a 40 mg test formulation was administered (feeding state) and dissolved in the buccal oral cavity for 10 minutes. To prevent opioid-related adverse events, subjects received naltrexone blockade. A total of 48 healthy adult male and female volunteers were enrolled. Forty-two of the 48 subjects enrolled in the first study completed the study (3 subjects experienced vomiting within 12 hours of dosing and 3 subjects received the required treatment. Did not end, so a total of 6 people were excluded from the PK analysis). Forty-four of the 48 subjects enrolled in the second study completed the study. However, the two subjects who completed the study developed vomiting within 12 hours of administration and were therefore excluded from the PK analysis.

The mean plasma oxycodone concentration (0 to 6 hours) obtained from the in vivo abuse tolerance test of the first example 8b is shown in FIG. The C _max and T _max values from the tests of the first and second example 8b based on mean plasma oxycodone concentration-time values are shown in Tables 93 and 94 below, respectively.

  As can be seen from these results, even if the OXY test capsule is held in the buccal cavity for 10 minutes, there is no difference in mean plasma concentration at the very early sampling time point between the buccal treatment and the whole treatment. As suggested, no rapid transmucosal absorption of oxycodone occurred. In addition, the overall degree of exposure to oxycodone was not affected by holding the OXY test capsule in the buccal oral cavity.

  The AQ of the OXY test capsule administered directly in this test was 7.5, while the AQ of the OXY test capsule after being held in the buccal oral cavity was 24.6. However, the AQ of the IR control was quite large (75.4), suggesting that the attractiveness of the abuse-resistant formulation is much less than the abuse of the oral solution of oxycodone.

Example 8c:
The effects of intense chewing on the rate and extent of absorption of 40 mg oxycodone base in an abuse-resistant oral formulation were compared to the same formulation swallowed as a whole (both fed) and an immediate release solution of oxycodone under fasted conditions. To compare and evaluate, the next in vivo abuse resistance evaluation test was a single center randomized crossover test. A total of 48 healthy subjects (29 men and 19 women) were enrolled in the study. To block opioid-related effects, subjects received naltrexone blockade. Four subjects (each two men and women) did not complete the study and therefore a total of 44 subjects were included in the PK analysis.

The PK results from this Example 8c test are reported in Table 95 below. In addition, plasma oxycodone concentration vs. FIG. 30 shows the cumulative percentage (average) with respect to the total area under the time curve data.

As can be seen from the above, the mean C _max was increased from 40.5 ng / mL to 82.3 ng / mL by vigorous chewing (chewing) of the OXY test capsules. However, in contrast to the IR control oral solution, the C _max of the chewed test capsule occurred significantly lower and significantly later in the later stages. Compared to the IR control oral solution of 1.07, the average T _max of the chewed OXY test capsules was reduced from 5.52 hours to 2.67 hours. The overall degree of absorption was not affected by chewing the OXY test capsule. From these data, chewing of the abuse-resistant formulation according to the present invention (normal abuse form) is a controlled release of the formulation, as evidenced by the absence of dose dumping and a plasma concentration profile with a broad plateau It is suggested that the mechanism was not invalidated.

  Finally, the AQ of the test capsule (as is) was 7.3 and the AQ of the chewed test capsule was 30.8. However, the AQ of the control oral solution was 95.3.

Example 8d:
To determine the rate and extent of absorption of 40 mg oxycodone base in an abuse-resistant oral formulation when co-administered with 240 mL 4% ethanol, 20% ethanol, and 40% ethanol compared to 240 mL water, The in vivo abuse tolerance evaluation test was a single center, four-way cross PK test (feeding state). A total of 37 healthy adult male and female female volunteers took at least one dose of the test formulation. To block opioid-related effects, subjects received naltrexone blockade. Many subjects experienced vomiting due to the high dose of alcohol. About 25% of subjects vomited after ingesting 20% ethanol, and 38% of subjects vomited after ingesting 40% ethanol. After vomiting, pharmacokinetic blood sampling over the given treatment period was discontinued. After the second treatment period of the study, any additional female subjects were determined not to take the test formulation with 40% ethanol. This is because all female subjects receiving this treatment vomited. Therefore, 40% ethanol treatment data is only available for 18 subjects.

In this study, the total volume of liquid given with the administration of the test formulation was 480 mL compared to 240 mL during the previous (Phase I) study. In the absence of alcohol, it is likely that a relatively large amount of water caused a physiological response of rapid gastric emptying, as demonstrated by a shorter T _max than that seen in previous studies.

The mean linear and semi-log plasma oxycodone concentration-time curves from this Example 8d study are shown in FIG. The values of C _max and T _max based on mean plasma oxycodone concentration-time values are shown in Table 96 below, and the average oxycodone PK parameters from non-compartmental analysis of the individual data of this Example 8d test are shown in Table 97 below. Show.

In this statistical analysis of Example 8d, the ratio of simultaneous intake with alcohol and simultaneous intake with water was calculated for maximum exposure (C _max ) and total exposure (AUC _last ), and these data are shown in Table 98 below. Show. As can be seen from the above, there was no significant effect of simultaneous ingestion of alcohol on the maximum exposure and the extent of oxycodone absorption from the abuse-resistant oral formulation according to the present invention.

The cumulative AUC (0-6 hours) data for oxycodone after administration of a single 40 mg OXY test capsule with water, 4% EtOH, 20% EtOH, and 40% EtOH is shown in FIG. As can be seen, the mean plasma concentration profiles across all treatment groups were similar and exhibited a typical controlled release pattern, so dose dumping as a result of simultaneous consumption with various contents of alcohol was It is suggested that it does not exist. In addition, a comparison of C _max and AUC _last between each ethanol treatment and water shows no effect (4% EtOH), a slight decrease in C _max (20% EtOH), and only the maximum alcohol content tested. A 10% increase in C _max (40% EtOH) was demonstrated.

Example 9: In vivo analysis of formulations (human clinical follow-up, pharmacokinetic study)
The following human clinical follow-up was conducted to evaluate the in vivo controlled release performance of abuse-resistant hydromorphone oral formulations prepared according to the present invention. In the study described below, plasma samples were analyzed for hydromorphone using a validated LC-MS-MS procedure.

Example 9a:
The abuse-resistant hydromorphone oral formulation used in this study was prepared using the following ingredients: Hydromorphone HCl, (“HMH”); Isopropyl myristate, NF (IPM); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); and cellulose acetate butyrate, grade 381-20 BP, ethanol wash ( Eastman Chemicals ("CAB"). A formulation is made using a commercial scale manufacturing method (process scheme 4 or 5 as described above) and then filled into a size 00 white impermeable gel cap shell to make a 16 mg formulation. Were used as test capsules. The details of this Example 9a HMH test capsule formulation are disclosed in Table 99 below.

  To examine the rate and extent of absorption of hydromorphone from a 16 mg content abuse-resistant oral formulation when administered in the fasted state and after meal intake, this human clinical trial was a single center food effect PK study. The comparison was for a single dose of 8 mg of Dilaudid brand hydromorphone HCl oral solution administered in the fasted state. The study was conducted with healthy adult male and adult female volunteers. There were 12 subjects in each study group (at feeding and fasting). To prevent opioid-related adverse events, subjects received naltrexone blockade. The feeding group was given a “standard” meal consisting of 8oz orange juice, two fried eggs, and two toasts with butter and jam.

The average PK from this Example 9a test is shown in Table 100 below. The results from the pharmacokinetic analysis are reported in Table 101 below.

  As can be seen from these results, food affects both the rate and extent of hydromorphone absorption from test abuse-resistant oral formulations. In this case, oral bioavailability is increased under fed conditions as compared to formulation administration during fasted conditions.

Example 9b:
The abuse-resistant hydromorphone oral formulation used in Example 9b was prepared using the following ingredients: Hydromorphone HCl (“HMH”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Labrafil M2125 CS (“LAB”); and cellulose acetate butyrate Grade 381-20 BP, Eastman Chemicals ("CAB"). Formulations were made using the GMP manufacturing method of Example 1d above (process scheme 8), then filled into size # 2 gel cap shells to make 8 and 16 mg formulations, which were used as HMH test capsules. Used as. The details of the formulation and formulation containing this Example 9b formulation are disclosed in Table 102 below.

Pharmacokinetics of 3 different HMH formulations (2 for QD, 1 for BID) of HMH test capsules HMH1-HMH3 versus the profile of IR control (Dilaudid) oral solution administered with QID (every 6 hours) This human clinical trial was a single center randomized crossover trial to investigate the pharmacological profile. There were 15 healthy male subjects in each test group. Since one subject dropped out of the IR control group, PK results were obtained from 14 subjects for that group alone. To prevent opioid-related adverse events, subjects received naltrexone blockade. Plasma samples were analyzed for hydromorphone using a validated LC-MS-MS procedure. The results from the pharmacokinetic analysis of this test 9b are reported in Table 103 below.

Example 10: In vivo analysis of formulations (human clinical follow-up, pharmacokinetic study)
In order to evaluate the in vivo controlled release performance of an abuse-resistant hydrocodone oral formulation prepared according to the present invention, the following human clinical follow-up was performed.

The abuse-resistant hydrocodone oral formulation used in Example 10 was prepared using the following ingredients. Hydrocodone bitartrate (“HCB”); Isopropyl myristate, NF (“IPM”); Colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); Butylated hydroxyl toluene, NF (“BHT”) ); Hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals), (“SAIB”); triacetin USP (“TA”); Gelucire 44/14 (Gattefose) (“GEL”); Cellulose acetate butyrate, grade 381-20 BP, Eastman Chemicals (“CAB”). A formulation was prepared using the GMP manufacturing method (Process Scheme 9) of Example 1e above, then filled into a size 3 gelcap shell to produce a formulation, which was used as a test capsule. Details of the formulation are disclosed in Table 104 below.

  To examine the pharmacokinetic profile and to further describe the effect of food on the rate and extent of hydrocodone absorption from a 15 mg abuse-resistant oral formulation made in accordance with the present invention, this human clinical trial was It was a single center randomized activator controlled crossover study. Subjects were randomly assigned to one of three treatment groups. The Feeding Treatment Group begins a standard breakfast (8 ounces of orange juice, 2 fried eggs, and 2 toasts with butter and jam) following an overnight fast for at least 8 hours 30 I received treatment after a minute. Two fasting groups received treatment after an overnight fast for at least 8 hours. All subjects received naltrexone blockade to prevent opioid-related adverse events. The activity control was a 30 mL dose of Lortab Elixir (hydrocodone tartrate / acetaminophen 7.5 mg / 500 mg per 15 mL), “IR Control”. Twenty-four healthy male subjects participated in the study, and PK analysis was performed on 22 subjects who completed the study. Plasma samples were analyzed for hydrocodone using a validated LC-MS-MS procedure.

The results from the pharmacokinetic analysis of this test 10b are reported in Table 105 below.

  As can be seen from these results, the average rate and extent of hydrocodone exposure after administration of the HCB test capsules increased under fed conditions as compared to fasted conditions. The rate of exposure and peak exposure after administration of the HCB test capsule was not as high as that seen with oral hydrocodone elixir (IR control).

Example 11: In vivo analysis of formulations (human clinical follow-up, pharmacokinetic study)
In order to evaluate the in vivo controlled release performance of an abuse-resistant amphetamine oral formulation prepared according to the present invention, the following human clinical follow-up was performed.

The abuse-resistant amphetamine oral formulation used in this Example 11 test was prepared using the following ingredients. D-Amphetamine sulfate (Cambrex) (“AMP”); isopropyl myristate, NF (“IPM”); colloidal silicon dioxide (Cabosil®, Cabot Corp) (“SiO ₂ ”); butylated hydroxyl toluene, NF (“BHT”); hydroxyethyl cellulose, NF (“HEC”); sucrose acetate isobutyrate (Eastman Chemicals) (“SAIB”); triacetin USP (“TA”); cellulose acetate butyrate, grade 381-20 BP , Ethanol wash ("CAB"); caprylocaproyl polyoxyglyceride ("Gattefose") ("CPG"); Gelucire 50/13 (Gattefosse) ("GEL"); and polyethylene glycol 8000 (Dow Chemical) ("PEG 8000"). Formulations are made using the GMP manufacturing process (process scheme 6 described in Example 1a above) and then filled into size # 1 gel capsules to make the formulations, which are used as AMP test capsules did. Detailed contents of the formulations are disclosed in Tables 106 and 107 below.

  To assess the safety and pharmacokinetic behavior of the three abuse-resistant amphetamine formulations and in healthy adult male and adult female volunteers under fed conditions, a commercial reference 15 mg content controlled release In order to evaluate the performance of these test capsules in contrast to d-amphetamine sulfate tablets (hereinafter “SR Control”), this human clinical trial is a single center randomized open label phase I It was a test. The test was conducted with 12 evaluable healthy subjects. Subjects were administered a single dose of each of the four test formulations separated by at least 7 days. Subjects were assigned to treatment using standard 4 × 4 Latin squares. Amphetamine levels in plasma samples were measured using a validated LC-MS-MS procedure.

The test results are shown in FIG. In this figure, the mean plasma concentration-time curve of amphetamine is shown. In addition, average pharmacokinetic values based on plasma concentration-time values are shown in Table 108 below.

  In all PK profiles, an absorption phase lasting about 6-7 hours was clearly visible. This was followed by the distribution phase and the discharge phase. Although all test formulations delivered the same dose of amphetamine, the AMP1 test capsules showed the lowest average profile of all four test formulations and the large individual differences in amphetamine concentrations. It is worth noting.

The time course of concentration change was very similar across the four treatment groups. Near-peak concentrations occur in about 6 hours in all treatment groups, and these near-peak concentrations are maintained for an additional about 24 hours. This profile is consistent between individuals. The formulation with the minimum C _max (AMP1 test capsule) tended to exhibit a T _max delay. The average terminal elimination half-life remained consistent regardless of the formulation administered.

  Calculation of the relative bioavailability of the AMP test capsules compared to a single dose of 15 mg amphetamine commercial product revealed that the AMP2 and AMP3 test capsules have similar relative bioavailability. . The relative bioavailability of each AMP test capsule compared to the SR control was as follows.

AMP1 (n = 14): 83.7 ± 25.4
AMP2 (n = 14): 99.0 ± 17.8
AMP3 (n = 13): 109.0 ± 13.6

This test was not designed to assess the bioequivalence of the AMP test capsule formulation, but AUC _t (Table 109), AUC _i (Table 110), and C _max (Table 111). A bioequivalence interval was constructed for the ln conversion ratio.

  The embodiments disclosed herein are merely exemplary and are not intended to limit the invention. The present invention should be construed only in light of the claims.

Claims (35)

A pharmacologically active agent;
・ High viscosity liquid carrier material (HVLCM),
・ Network-former,
・ Rheology modifier,
A hydrophilic agent, and a solvent,
An oral pharmaceutical formulation comprising: a controlled release carrier system comprising:   The preparation according to claim 1, wherein the pharmacologically active agent is an opioid, a central nervous system (CNS) inhibitor, or a CNS stimulant.   The formulation according to claim 2, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone in either the free base form or a pharmaceutically acceptable salt form thereof.   The formulation of claim 2, wherein the pharmacologically active agent is selected from amphetamine, methylphenidate, and pharmaceutically acceptable salts thereof.   5. A formulation according to any of claims 1-4, wherein the controlled release carrier system further comprises a viscosity enhancing agent.   6. The formulation of claim 5, wherein the viscosity enhancing agent is silicon dioxide. A pharmacologically active agent;
・ HVLCM,
・ Network-former,
A first viscosity enhancer,
A hydrophilic solvent, and a hydrophobic solvent,
An oral pharmaceutical formulation comprising: a controlled release carrier system comprising:   The preparation according to claim 7, wherein the pharmacologically active agent is an opioid, a central nervous system (CNS) inhibitor, or a CNS stimulant.   9. A formulation according to claim 8, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone in either the free base form or a pharmaceutically acceptable salt form thereof.   11. The formulation of claim 10, wherein the pharmacologically active agent is selected from amphetamine, methylphenidate, and pharmaceutically acceptable salts thereof. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The pharmaceutical formulation is resistant to abuse, and the formulation is suitable for twice daily administration (BID),
The above preparation.   12. The formulation of claim 11, wherein the active agent is oxycodone, oxymorphone, hydrocodone, or hydromorphone.   13. A formulation according to claim 12, wherein the opioid is oxycodone.   14. A formulation according to any of claims 11 to 13, wherein the active agent is present in free base form.   14. A formulation according to any of claims 11 to 13, wherein the active agent is present in salt form.   16. A formulation according to any of claims 11 to 15, wherein the controlled release carrier system further provides a reduced risk of misuse or abuse.   17. A formulation according to claim 16, wherein the reduced risk of misuse or abuse is characterized by a low in vitro solvent extraction rate of active agent from the formulation.   The reduced risk of misuse or abuse is characterized by having no significant effect on the absorption of active agent from the formulation when a subject takes the formulation and alcohol simultaneously. The preparation described in 1.   The reduced risk of misuse or abuse is further characterized by not having any significant effect on the absorption of active agent from the formulation when a subject takes the formulation and alcohol at the same time. The formulation according to 17.   20. A formulation according to any of claims 11 to 19, wherein in vivo absorption of the active agent from the formulation is enhanced when the formulation is administered with food. An oral pharmaceutical formulation comprising a pharmacologically active agent and a controlled release carrier system,
The controlled release carrier system comprises HVLCM, a network former, a rheology modifier, and a hydrophilic agent, and the formulation is abuse-resistant,
The above preparation.   24. The formulation of claim 21, wherein the controlled release carrier system further comprises a viscosity enhancing agent.   The formulation of claim 22, wherein the hydrophilic agent also functions as a second viscosity enhancer.   The preparation according to any one of claims 21 to 23, wherein the hydrophilic agent is hydroxyethyl cellulose (HEC).   25. A formulation according to any of claims 21 to 24, wherein the HVLCM is sucrose acetate isobutyrate (SAIB).   The formulation according to any of claims 21 to 25, further comprising a solvent.   27. The formulation of claim 26, wherein the solvent is triacetin.   The formulation of claim 22, wherein the viscosity enhancing agent is silicon dioxide.   The preparation according to any one of claims 21 to 28, wherein the network structure-forming agent is cellulose acetate butyrate (CAB).   30. A formulation according to any of claims 21 to 29, wherein the rheology modifier is isopropyl myristate (IPM).   The formulation according to any of claims 21 to 30, further comprising a stabilizer.   32. The formulation of claim 31, wherein the stabilizer is butylhydroxyl toluene (BHT).   The preparation according to any one of claims 21 to 32, wherein the pharmacologically active agent is an opioid, a central nervous system (CNS) inhibitor, or a CNS stimulant.   34. The formulation of claim 33, wherein the pharmacologically active agent is selected from oxycodone, oxymorphone, hydrocodone, hydromorphone in either the free base form or a pharmaceutically acceptable salt form thereof.   34. The formulation of claim 33, wherein the pharmacologically active agent is selected from amphetamine, methylphenidate, and pharmaceutically acceptable salts thereof.

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